Pharmaceutical compositions comprising brexpiprazole and methods of making the same

Abstract

The application provides a medicine composition for injection and a preparation method thereof, in particular provides a medicine composition containing brexpiprazole, and further provides a biodegradable polymer and a preparation method thereof. The medicine composition for injection and the biodegradable polymer provided by the application have a slow-release effect, can realize slow release of brexpiprazole in the body, can realize once-a-month administration, and have the advantages of improving patient compliance and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to pharmaceutical compositions containing birepiperazole, methods for preparing the same, and pharmaceutical uses of the pharmaceutical compositions. Background Technology

[0002] Brepiperazole, chemical name: 7-[4-(4-benzo[b]thiophene-4-yl-piperazin-1-yl)butoxy]-1H-quinoline-2-one, was jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharmaceuticals Ltd. of Denmark. It was approved by the FDA in July 2015 for the treatment of major depressive disorder (MDD) and schizophrenia. It is available in oral tablets in strengths of 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg and 4 mg.

[0003] Biriperazole is a partial agonist of 5-HT1A and dopamine D2 receptors and an antagonist of 5-HT2A receptors. Compared to aripiprazole, biriperazole has lower intrinsic dopamine D2 receptor activity, higher binding affinity to 5-HT1 and 5-HT2 receptors, fewer extrapyramidal side effects, and fewer akathisia side effects, making it a first-line drug for the treatment of schizophrenia. Biriperazole tablets, taken orally once daily, must disintegrate in the stomach before releasing the drug, resulting in a slow onset of action and limited bioavailability. Furthermore, its clinical use faces several challenges. For example, schizophrenia has a long course, and the currently available biriperazole tablets require frequent dosing, leading to issues such as medication hoarding and missed doses. Developing a long-acting biriperazole formulation is of significant clinical importance in improving patient adherence and long-term treatment compliance, increasing treatment effectiveness, and preventing relapse and disease progression.

[0004] Currently disclosed development schemes for long-acting birepiperazole injections mainly include: CN107536802A discloses a suspension containing birepiperazole or its salts aggregated into secondary particles. This solution addresses the poor stability of the suspension by controlling particle size and adding a binder. The suspension disclosed in this patent can achieve sustained release of birepiperazole for at least one week. Although aqueous suspensions have sustained-release characteristics, in vivo blood drug concentration measurements in rats show slow initial drug release and large fluctuations in blood drug concentration, making it difficult to maintain a stable and effective blood drug concentration, resulting in no significant clinical advantage.

[0005] CN108186556A discloses a gel composition containing aripiprazole or ipiliprazole. This gel composition suspends bripiprazole in a carrier solution, which is then pulverized to the desired particle size to form a gel-like suspension system suitable for intramuscular or subcutaneous injection. The dosage cycle for this formulation can be once every one, two, or three months. However, this patent only discloses animal test data for aripiprazole and does not disclose data regarding the long-acting release of bripiprazole.

[0006] WO2018233148A1 discloses an in-situ gel formulation composed of phospholipids, Span 80, a pharmaceutical active ingredient, and an ethanol solution, wherein the pharmaceutical active ingredient is biriperazole; by weight, it consists of 0.01-20 parts of biriperazole, 30-60 parts of phospholipids, 10-40 parts of Span, and 7-30 parts of ethanol solution; wherein the concentration range of the ethanol solution is 70-100% (v / v), and in vivo rat experiments show that the release time can last for 25 days. After intramuscular injection, the formulation disclosed in this patent has a significant burst release, followed by less drug release and large fluctuations in blood drug concentration.

[0007] CN111603439A discloses a long-acting buripiperazole injection and its preparation method, comprising the active pharmaceutical ingredient buripiperazole, a gel matrix phospholipid, a biocompatible solvent N-methyl-2-pyrrolidone, and an injection oil; the in-situ gel injection disclosed in this patent has a slow release, is prone to drug accumulation and retention in the body, and also has potential risks such as formulation stability and irritation.

[0008] CN107213136A, CN106963746A, and CN106822039A disclose a long-acting injection of birepiperazole using PLGA microspheres as a carrier. However, this technology generally has a low drug loading capacity, requires the use of toxic and harmful organic solvents such as dichloromethane in its preparation process, carries a high risk of solvent residue, and is complex, making it unsuitable for industrial production. Furthermore, it lacks corresponding in vivo experimental data to support the achievement of a long-acting effect.

[0009] Although various long-acting injectable formulations of biriperazole have been developed, they generally suffer from one or more defects, such as significant burst release, unstable duration of action, large fluctuations in blood drug concentration, high peak-to-trough ratio, and poor stability. To date, no long-acting biriperazole injectable formulation that meets clinical needs has been approved for marketing. Therefore, there is still an urgent need in the field to develop a suitable long-acting biriperazole injectable formulation to meet clinical needs. Summary of the Invention

[0010] In view of the above-mentioned problems existing in the prior art, the purpose of the present invention is to provide a novel long-acting drug composition of birepiperazole that can be injected subcutaneously. The drug composition containing birepiperazole provided by the present invention has excellent in vivo PK curve, stable blood drug concentration, and can maintain an effective blood drug concentration for about 1 month. Moreover, its preparation method is simple and suitable for industrial application.

[0011] Specifically, a first aspect of the present invention provides a pharmaceutical composition for injection, the pharmaceutical composition comprising: (a) Buripiperazole or a pharmaceutically acceptable salt thereof; (b) A biodegradable copolymer comprising at least one of a diblock copolymer or a triblock copolymer; The diblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 200-50000 Da, preferably with a number average molecular weight of 200-1500 Da. The triblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 200-50000 Da, preferably with a number average molecular weight of 200-4500 Da. (c) A water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol or isopropanol; Preferably, the pharmaceutical composition comprises, by weight, 5-35% birepiperazole or a pharmaceutically acceptable salt thereof, 10-45% a biodegradable copolymer, and 35-80% a water-soluble organic solvent.

[0012] More preferably, the pharmaceutical composition comprises 10-35% by weight of birepiperazole or a pharmaceutically acceptable salt thereof; More preferably, the pharmaceutical composition comprises 10-40% by weight of a biodegradable copolymer; More preferably, the pharmaceutical composition contains 35-70% by weight of a water-soluble organic solvent.

[0013] In some preferred embodiments, the injectable pharmaceutical composition of the present invention comprises 5-35% by weight of biriperazole or a pharmaceutically acceptable salt thereof, preferably 10-35% by weight of biriperazole or a pharmaceutically acceptable salt thereof; for example, comprising 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or 19% by weight. The pharmaceutical composition comprises 20% by weight, 21% by weight, 22% by weight, 23% by weight, 24% by weight, 25% by weight, 26% by weight, 27% by weight, 28% by weight, 29% by weight, 30% by weight, 31% by weight, 32% by weight, 33% by weight, 34% by weight, or 35% by weight of biriperazole or a pharmaceutically acceptable salt thereof, and values ​​between any two numbers; preferably, the pharmaceutical composition comprises 5 to 30% by weight of biriperazole or a pharmaceutically acceptable salt thereof, and more preferably, the pharmaceutical composition comprises 15 to 30% by weight of biriperazole or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the pharmaceutical composition for injection contains 5% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the pharmaceutical composition for injection contains 7% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the pharmaceutical composition for injection of the present invention comprises 15% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the pharmaceutical composition for injection described in this invention comprises 17% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the pharmaceutical composition for injection of the present invention comprises 18% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the pharmaceutical composition for injection described in this invention comprises 20% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the pharmaceutical composition for injection described in this invention comprises 30% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the pharmaceutical composition comprises 10-45% by weight of a biodegradable copolymer, for example, comprising 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 3% by weight. Biodegradable copolymers comprising 6% by weight, 37% by weight, 38% by weight, 39% by weight, 40% by weight, 41% by weight, 42% by weight, 43% by weight, 44% by weight, 45% by weight, 10-45% by weight, 10-40% by weight, 15-40% by weight, 15-35% by weight, 10-35% by weight, 15-35% by weight, 10-25% by weight, 10-20% by weight, 10-15% by weight, 15-25% by weight, or 15-20% by weight, etc.; preferably, the pharmaceutical composition comprises 15-40% by weight of biodegradable copolymers.

[0022] In some embodiments, the biodegradable copolymer comprises a diblock copolymer.

[0023] In some embodiments, the biodegradable copolymer comprises a triblock copolymer.

[0024] In some embodiments, the biodegradable copolymer comprises diblock copolymers and triblock copolymers.

[0025] In some embodiments, the biodegradable copolymer comprises a diblock copolymer and a triblock copolymer, wherein the diblock copolymer content is 10-45% by weight, preferably 10-25% by weight, and the triblock copolymer content is 0-45% by weight, preferably 5-15% by weight, based on the total weight of the pharmaceutical composition, and the total amount of the diblock copolymer and triblock copolymer in the pharmaceutical composition is 10-45% by weight, preferably 10-40% by weight, for example 15-40% by weight.

[0026] In some preferred embodiments, the biodegradable copolymer of the present invention comprises a combination of diblock copolymers and triblock copolymers; wherein, based on the total weight of the pharmaceutical composition, the content of the diblock polymer in the pharmaceutical composition is 5-30% by weight, for example, the content of the diblock polymer in the pharmaceutical composition is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 10-30%, 10-25%, 10-30%, 10-25%, 10-30%. The content of the diblock polymer in the pharmaceutical composition is preferably 10-25% by weight, or 10-15% by weight, or any range between two numbers; wherein the content of the triblock polymer in the pharmaceutical composition is 1-20% by weight, for example, the content of the triblock polymer in the pharmaceutical composition is 1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% by weight, or any range between two numbers; preferably, the content of the triblock polymer in the pharmaceutical composition is 5-20% by weight, or 5-15% by weight, or 7-13% by weight.

[0027] In some embodiments, the biodegradable copolymer of the present invention is a diblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 10-30% by weight, preferably 10-20% by weight.

[0028] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 10-30% by weight and the content of the triblock copolymer is 5-20% by weight.

[0029] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 10-30% by weight and the content of the triblock copolymer is 5-15% by weight.

[0030] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 10-25% by weight and the content of the triblock copolymer is 5-15% by weight.

[0031] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 10-20% by weight and the content of the triblock copolymer is 5-15% by weight.

[0032] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 15-25% by weight and the content of the triblock copolymer is 5-15% by weight.

[0033] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 10-20% by weight and the content of the triblock copolymer is 7-13% by weight.

[0034] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 15-16% by weight and the content of the triblock copolymer is 9-10% by weight.

[0035] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 16-17% by weight and the content of the triblock copolymer is 10-11% by weight.

[0036] In some embodiments, the biodegradable copolymer of the present invention is a combination of diblock copolymer and triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 19-20% by weight and the content of the triblock copolymer is 12-13% by weight.

[0037] In some embodiments, the biodegradable copolymer of the present invention is a combination of a diblock copolymer and a triblock copolymer; wherein the content of the diblock polymer in the pharmaceutical composition is 25-26% by weight and the content of the triblock copolymer is 6-7% by weight.

[0038] The diblock copolymers described in the context of this invention comprise polylactic acid (PLA) and polyethylene glycol (PEG); the polylactic acid (PLA) in the diblock copolymer is composed of D-lactic acid or L-lactic acid monomer units, or is composed of randomly distributed D-lactic acid and L-lactic acid monomer units.

[0039] The terminal hydroxyl groups at one end of the polyethylene glycol (PEG) chain in the diblock copolymer are capped. For example, the terminal hydroxyl groups at one end of the polyethylene glycol (PEG) chain are capped by C 1~3 The PEG chain is capped with alkyl, carbamoyl, ester, or amide groups, while the terminal hydroxyl group at the other end of the PEG chain forms an ester bond with the polylactic acid (PLA) chain.

[0040] Further preferably, the terminal hydroxyl groups at one end of the polyethylene glycol (PEG) chain in the diblock copolymer are C 1~3 Alkyl-terminated, preferably, the C 1~3 The alkyl group is methyl (-CH3), ethyl (-CH2CH3) or isopropyl, etc., more preferably methyl.

[0041] In some embodiments, the terminal hydroxyl groups at one end of the polyethylene glycol (PEG) chain in the diblock copolymer are capped with methyl groups (-CH3), and this capping can be referred to as mPEG, while the terminal hydroxyl groups at the other end of the PEG chain form ester bonds with polylactic acid (PLA) chains. Typically, the diblock copolymer can be obtained by ring-opening polymerization of D,L-lactide initiated by the terminal hydroxyl groups of the mPEG chain.

[0042] In some embodiments, the diblock copolymer of the present invention is preferably a block copolymer of mPEG and PLA in which the terminal hydroxyl groups at one end of the polyethylene glycol (PEG) chain are capped with methyl (-CH3), having the structure shown in Formula I: , Where n represents the number of repeating units of ethylene oxide (-CH2CH2O-) in polyethylene glycol (PEG), and m is the number of repeating units of lactic acid in polylactic acid (PLA); the theoretical molecular weight of the diblock copolymer can be calculated using the molar mass of lactic acid units (M(LA) = 72 g / mol) and ethylene oxide units (M(EO) = 44 g / mol) as well as the number of repeating units in each block. For example, the theoretical molecular weight calculation formula for mPEG-PLA copolymer is as follows: MW(mPEG-PLA) = n 44+m 72+32.

[0043] The molecular weight range of end-capped polyethylene glycol can be from 100 Da to 10000 Da, or 100 Da to 3000 Da, or 100 Da to 1000 Da, or 200 Da to 3000 Da, or 200 Da to 2000 Da, or 200 Da to 3000 Da, or 300 Da to 3000 Da, or 300 Da to 2000 Da, or 300 Da to 1000 Da, or 300 Da to 500 Da, or 350 Da to 2000 Da, etc. For example, the end-capped polyethylene glycol has a mass of 100 Da, 150 Da, 200 Da, 250 Da, 300 Da, 350 Da, 400 Da, 450 Da, 500 Da, 550 Da, 600 Da, 650 Da, 700 Da, 750 Da, 800 Da, 850 Da, 900 Da, 950 Da, 1000 Da, 1500 Da, 2000 Da, 2500 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 6000 Da, 7000 Da, 8000 Da, 9000 Da, or 10000 Da, etc. Preferably, the molecular weight range of the end-capped polyethylene glycol is 100 Da to 500 Da, or 200 Da to 500 Da, or 200 Da to 400 Da, or 200 Da to 350 Da, etc.

[0044] The molecular weight range of polylactic acid in diblock copolymers can be from 100 Da to 50,000 Da, for example, 100 Da, 150 Da, 200 Da, 250 Da, 300 Da, 350 Da, 400 Da, 450 Da, 500 Da, 550 Da, 600 Da, 650 Da, 700 Da, 750 Da, 800 Da, 850 Da, 900 Da, 950 Da, 1000 Da, 1100 Da, 1150 Da, 1200 Da, 1250 Da, 1300 Da, 1350 Da, 1400 Da. Da, 1500Da, 2000Da, 2500Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da, 10000Da, 15000Da, 16000Da, 17000Da, 18000Da, 19000Da, 20000Da, 30000Da, 40000Da, 50000Da, or 100Da to 3000Da, or 100Da to 1000Da. Alternatively, the molecular weight of polylactic acid in the diblock copolymer can range from 100 Da to 500 Da, or 200 Da to 3000 Da, or 200 Da to 2000 Da, or 200 Da to 3000 Da, or 300 Da to 3000 Da, or 350 Da to 2000 Da, or 300 Da to 2000 Da, or 300 Da to 1000 Da, or 300 Da to 400 Da, or 300 Da to 500 Da, etc.; preferably, the molecular weight of polylactic acid in the diblock copolymer is in the range of 100 Da to 30000 Da, for example, 100 Da to 19600 Da. Alternatively, the molecular weight of polylactic acid in the diblock copolymer may be 100 Da to 1150 Da, or 200 Da to 1150 Da, or 1150 Da to 19600 Da, or 100 Da to 2000 Da, or 100 Da to 3000 Da, or 100 Da to 4000 Da; more preferably, the molecular weight of polylactic acid in the diblock copolymer may be 100 Da to 1200 Da, or 100 Da to 1150 Da, or 100 Da to 800 Da, or 100 Da to 600 Da, or 100 Da to 200 Da, or 300 Da to 600 Da, etc.

[0045] More preferably, the number-average molecular weight of the diblock copolymer is 200-30000 Daltons (Da), for example, 200Da, 300Da, 400Da, 500Da, 600Da, 700Da, 800Da, 900Da, 1000Da, 1100Da, 1200Da, 1300Da, 1400Da, 1500Da, 1600Da, 1700Da, 1800Da, 1900Da, 2000Da, 2100Da, 2200Da, 2300Da, 2400Da, 2500Da, 2600Da, 2700Da, 2800Da, and 2900Da. a. 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 5500Da, 6000Da, 6500Da, 7000Da, 7500Da, 8000Da, 8500Da, 9000Da, 10000Da, 15000Da, 20000Da, 21000Da, 215000Da, 22000Da, 23000Da, 24000Da, 25000Da, 26000Da, 27000Da, 28000Da, 29000Da, or 30000Da, etc., and any range between two numbers, such as 300~25000. The number average molecular weight of the diblock copolymer is preferably 200-1500 Da, 200-1000 Da, or 200-500 Da; more preferably 300-1500 Da, 300-1000 Da, or 300-800 Da.

[0046] In some embodiments, the number-average molecular weight of the diblock copolymer is 200-1500 Da; more preferably, the diblock copolymer is mPEG-PLA, wherein the molecular weight of mPEG is about 100-500 Da and the molecular weight of PLA is about 100-1200 Da.

[0047] In some embodiments, the number-average molecular weight of the diblock copolymer is about 1500 Da; more preferably, the diblock copolymer is mPEG-PLA, wherein the molecular weight of mPEG is about 350 Da and the molecular weight of PLA is about 1150 Da.

[0048] In some embodiments, the number-average molecular weight of the diblock copolymer is about 4260 Da; more preferably, the diblock copolymer is mPEG-PLA, wherein the molecular weight of mPEG is about 1000 Da and the molecular weight of PLA is about 3260 Da.

[0049] In some embodiments, the number-average molecular weight of the diblock copolymer is about 21,600 Da; more preferably, the diblock copolymer is mPEG-PLA, wherein the molecular weight of mPEG is about 2,000 Da and the molecular weight of PLA is about 19,600 Da.

[0050] In some embodiments, the number-average molecular weight of the diblock copolymer is about 300 Da; more preferably, the diblock copolymer is mPEG-PLA, wherein the molecular weight of mPEG is about 200 Da and the molecular weight of PLA is about 100 Da.

[0051] In some embodiments, the number-average molecular weight of the diblock copolymer is about 800 Da; more preferably, the diblock copolymer is mPEG-PLA, wherein the molecular weight of mPEG is about 200 Da and the molecular weight of PLA is about 600 Da.

[0052] In some embodiments, the diblock copolymer comprises 5 to 70 wt% polyethylene glycol, for example, the diblock copolymer comprises 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 15 wt%, 20 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, or 5 to 35 wt%, or 5 to 67 wt%, or 9 to 66.7 wt%, or 20 to 70 wt% of polyethylene glycol, preferably mPEG.

[0053] In some embodiments, the diblock copolymer comprises 30-95% by weight of polylactic acid, for example, the diblock copolymer comprises 30%, 35%, 40%, 45%, 50%, 55%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, or 5-35%, or 30-80%, or 30-91%, or 30-77%, or 33-91% by weight of polylactic acid, etc., preferably the diblock copolymer comprises 30-80% by weight of polylactic acid, or 33-77% by weight of polylactic acid.

[0054] In some embodiments, the diblock copolymer comprises 9-25% by weight polyethylene glycol and 75-95% by weight polylactic acid, preferably mPEG.

[0055] In some embodiments, the diblock copolymer comprises 9-15% by weight polyethylene glycol and 85-91% by weight polylactic acid, preferably mPEG.

[0056] In some embodiments, the diblock copolymer comprises 9-10% by weight polyethylene glycol and 90-91% by weight polylactic acid, preferably mPEG.

[0057] In some embodiments, the diblock copolymer comprises 20-25% by weight polyethylene glycol and 75-80% by weight polylactic acid, preferably mPEG.

[0058] In some embodiments, the diblock copolymer comprises 60-70% by weight polyethylene glycol and 30-40% by weight polylactic acid, preferably mPEG.

[0059] In the context of this invention, the triblock copolymer comprises polylactic acid (PLA) and polyethylene glycol (PEG); the PLA is composed of D-lactic acid or L-lactic acid monomer units, or of randomly distributed D-lactic acid and L-lactic acid monomer units. The triblock copolymer is obtained by forming ester bonds between the terminal hydroxyl groups at both ends of the polyethylene glycol (PEG) chain and the PLA chain. Typically, the triblock copolymer can be obtained by ring-opening polymerization of D,L-lactide initiated by the terminal hydroxyl groups of the PEG chain.

[0060] In some embodiments, the triblock copolymer has the structure shown in Formula II: , Where y represents the number of repeating units of ethylene oxide (-CH2CH2O-) in polyethylene glycol (PEG), and x represents the number of repeating units of lactic acid in polylactic acid (PLA). The theoretical molecular weight of the triblock copolymer can be calculated using the molar masses of lactic acid units (M(LA), 72 g / mol) and ethylene oxide units (M(EO), 44 g / mol) as well as the number of repeating units in each block, as follows: MW(PLA-PEG-PLA)=y 44+2 x 72+18.

[0061] The molecular weight range of polyethylene glycol in triblock copolymers can be from 100 Da to 10000 Da, or 100 Da to 5000 Da, or 200 Da to 10000 Da, or 200 Da to 5000 Da, or 200 Da to 4000 Da, or 200 Da to 3000 Da, or 200 Da to 2000 Da, or 300 Da to 10000 Da, or 300 Da to 5000 Da, or 300 Da to 4000 Da, or 300 Da to 3000 Da, or 300 Da to 2000 Da, or 400 Da. The range is as follows: a to 5000Da, or 400Da to 4000Da, or 400Da to 3000Da, or 400Da to 2000Da, or 500Da to 10000Da, or 500Da to 5000Da, or 500Da to 4000Da, or 500Da to 3000Da, or 500Da to 2000Da, or 1000Da to 3000Da, or 100Da to 2000Da, or 200Da to 2000Da, or 200Da to 1000Da, or 200Da to 500Da, etc. For example, the molecular weight of polyethylene glycol in triblock copolymers is 100 Da, 200 Da, 300 Da, 400 Da, 500 Da, 600 Da, 700 Da, 800 Da, 900 Da, 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, and 2000 Da. a. 2100Da, 2200Da, 2300Da, 2400Da, 2500Da, 2600Da, 2700Da, 2800Da, 2900Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da, or 10000Da, as well as the range between any two numbers.

[0062] The molecular weight of polylactic acid in triblock copolymers can range from 100 Da to 50,000 Da, for example, 100 Da, 200 Da, 300 Da, 400 Da, 500 Da, 600 Da, 700 Da, 800 Da, 900 Da, 1000 Da, 1100 Da, 1200 Da, 1300 Da, 1400 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 1900 Da, 2000 Da, 2100 Da, 2200 Da. 0Da, 2300Da, 2400Da, 2500Da, 2600Da, 2700Da, 2800Da, 2900Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da, 1000Da, 1500Da, 2000Da, 2500Da, 3000Da, 3100Da, 3150Da, 3200Da, 3250 Da, 3260Da, 3300Da, 3350Da, 3400Da, 3450Da, 3500Da, 3550Da, 3600Da, 3650Da, 3700Da, 3750Da, 3800Da, 3 900Da, 4000Da, 4500Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da, 9500Da, 9800Da, 10000Da, 15000Da, 160 The molecular weight range of polylactic acid in the triblock copolymer is preferably 100 Da to 1500 Da, more preferably 100 Da to 1000 Da, for example 100 Da to 600 Da. The ranges are 00 Da, 17000 Da, 18000 Da, 19000 Da, 19600 Da, 20000 Da, 30000 Da, 40000 Da or 50000 Da, or 200 Da to 30000 Da, or 200 Da to 20000 Da, or 200 Da to 4000 Da, etc.

[0063] More preferably, the number-average molecular weight of the triblock copolymer is 200-50000 Daltons (Da), for example, 200Da, 300Da, 400Da, 500Da, 600Da, 700Da, 800Da, 900Da, 1000Da, 1100Da, 1200Da, 1300Da, 1400Da, 1500Da, 1600Da, 1700Da, 1800Da, 1900Da, 2000Da, 2100Da, 2200Da, 2300Da, 2400Da, 2500Da, 2600Da, 2700Da, 2800Da, 2... 900Da, 3000Da, 3500Da, 4000Da, 4500Da, 5000Da, 6000Da, 7000Da, 8000Da, 9000Da, 1000Da, 1100Da, 1500Da, 2000Da, 2100Da, 2200Da, 2 300Da, 2400Da, 2500Da, 2600Da, 2700Da, 2800Da, 2900Da, 3000Da, 3500Da, 4000Da, 4100Da, 4200Da, 4250Da, 4260Da, 4270Da, 4300Da, 4 400Da, 4500Da, 4600Da, 4700Da, 4800Da, 4900Da, 5000Da, 5500Da, 6000Da, 6500Da, 7000Da, 7500Da, 8000Da, 8500Da, 9000Da, 10000Da , 15000Da, 20000Da, 21000Da, 21500Da, 21600Da, 22000Da, 23000Da, 24000Da, 25000Da, 26000Da, 27000Da, 28000Da, 29000Da, 30000Da The number average molecular weight of the triblock copolymer is preferably 100~4500Da, or 100~800Da, more preferably 300~1500Da, or 300~1000Da, or 300~800Da, etc., with a molecular weight of 40000Da or 50000Da, or 400Da to 30000Da, or 400~10000Da, or 300~1000Da, or 400~4260Da, etc.

[0064] In some embodiments, the number-average molecular weight of the triblock copolymer is 200 to 4500 Da; more preferably, the triblock copolymer is PLA-PEG-PLA, wherein the molecular weight of PEG is about 100 to 1000 Da, and the molecular weight of PLA is about 100 to 3500 Da.

[0065] In some embodiments, the number-average molecular weight of the triblock copolymer is 200-1500 Da; more preferably, the triblock copolymer is PLA-PEG-PLA, wherein the molecular weight of PEG is about 100-500 Da and the molecular weight of PLA is about 100-1200 Da.

[0066] In some embodiments, the number-average molecular weight of the triblock copolymer is about 4260 Da; more preferably, the triblock copolymer is PLA-PEG-PLA, wherein the molecular weight of PEG is about 1000 Da and the molecular weight of PLA is about 3260 Da.

[0067] In some embodiments, the number-average molecular weight of the triblock copolymer is about 21,600 Da; more preferably, the triblock copolymer is PLA-PEG-PLA, wherein the molecular weight of PEG is about 2,000 Da and the molecular weight of PLA is about 19,600 Da.

[0068] In some embodiments, the number-average molecular weight of the triblock copolymer is about 400 Da; more preferably, the triblock copolymer is PLA-PEG-PLA, wherein the molecular weight of PEG is about 200 Da and the molecular weight of PLA is about 200 Da.

[0069] In some embodiments, the number-average molecular weight of the triblock copolymer is about 800 Da; more preferably, the triblock copolymer is PLA-PEG-PLA, wherein the molecular weight of PEG is about 200 Da and the molecular weight of PLA is about 600 Da.

[0070] In some embodiments, the triblock copolymer comprises 5 to 50% by weight of polyethylene glycol, for example, the triblock copolymer comprises 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, or 50% by weight of polyethylene glycol; preferably, the triblock copolymer comprises 7 to 50% by weight of polyethylene glycol, for example, 9 to 50% by weight, or 20 to 50% by weight.

[0071] In some embodiments, the triblock copolymer comprises 50-95% by weight of polylactic acid, for example, the triblock copolymer comprises 50%, 55%, 60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% by weight of polylactic acid, preferably 50-91% by weight, or 50-77% by weight of polylactic acid, and more preferably 50-75% by weight of polylactic acid.

[0072] In some embodiments, the triblock copolymer comprises 9 to 25% by weight polyethylene glycol and 75 to 95% by weight polylactic acid.

[0073] In some embodiments, the triblock copolymer comprises 9-15% by weight polyethylene glycol and 85-91% by weight polylactic acid.

[0074] In some embodiments, the triblock copolymer comprises 9-10% by weight polyethylene glycol and 90-91% by weight polylactic acid.

[0075] In some embodiments, the triblock copolymer comprises 20-25% by weight polyethylene glycol and 75-80% by weight polylactic acid.

[0076] In some embodiments, the triblock copolymer comprises 25-50% by weight polyethylene glycol and 50-75% by weight polylactic acid.

[0077] In some embodiments, the triblock copolymer comprises 30-60% by weight polyethylene glycol and 40-70% by weight polylactic acid.

[0078] In some embodiments, the triblock copolymer comprises 45-55% by weight polyethylene glycol and 45-55% by weight polylactic acid.

[0079] In some embodiments, the number-average molecular weight of the diblock polymer is 200-30000 Da, preferably 300-25000 Da, and the diblock polymer contains 30-95% by weight of polylactic acid, preferably 30-80% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0080] In some embodiments, the diblock polymer has a number-average molecular weight of 21,600 Da and contains 75-93% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0081] In some embodiments, the diblock polymer has a number-average molecular weight of 1500 Da and contains 70-80% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0082] In some embodiments, the number-average molecular weight of the diblock polymer is 200-3000 Da, preferably 300-2000 Da, and the diblock polymer contains 30-80% by weight of polylactic acid, preferably 30-77% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0083] In some embodiments, the number-average molecular weight of the diblock polymer is 100-1500 Da, preferably 300-1500 Da, and the diblock polymer contains 30-80% by weight of polylactic acid, preferably 30-75% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0084] In some embodiments, the diblock polymer has a number-average molecular weight of about 300 Da and contains 30-40% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0085] In some embodiments, the diblock polymer has a number-average molecular weight of about 800 Da and contains 20-30% by weight of polylactic acid; more preferably, the diblock polymer has a structure as shown in Formula I above.

[0086] In some embodiments, the number average molecular weight of the triblock is 200-30000 Da, preferably 300-25000 Da; the polylactic acid content in the triblock polymer is 50-95% by weight, preferably 50-91% by weight; more preferably, the triblock polymer has the structure shown in Formula II above.

[0087] In some embodiments, the number-average molecular weight of the triblock is 4260 Da; the polylactic acid content in the triblock polymer is 65-95% by weight, preferably 70-80% by weight; and more preferably, the triblock polymer has the structure shown in Formula II above.

[0088] In some embodiments, the number-average molecular weight of the triblock is 21,600 Da; the polylactic acid content in the triblock polymer is 65-95% by weight, preferably 75-93% by weight; more preferably, the triblock polymer has the structure shown in Formula II above.

[0089] In some embodiments, the number average molecular weight of the triblock is 200-5000 Da, preferably 400-5000 Da; the polylactic acid content in the triblock polymer is 50-95% by weight, preferably 50-80% by weight; and more preferably, the triblock polymer has the structure shown in Formula II above.

[0090] In some embodiments, the number-average molecular weight of the triblock is 200-4500 Da, preferably 300-1500 Da; the polylactic acid content in the triblock polymer is 50-80% by weight, preferably 50-75% by weight; and more preferably, the triblock polymer has the structure shown in Formula II above.

[0091] In some embodiments, the number-average molecular weight of the triblock is about 400 Da; the polylactic acid content in the triblock polymer is 45-55% by weight, preferably 50% by weight; and more preferably, the triblock polymer has the structure shown in Formula II above.

[0092] In some embodiments, the number-average molecular weight of the triblock is about 800 Da; the polylactic acid content in the triblock polymer is 50-80% by weight, preferably 75% by weight; more preferably, the triblock polymer has the structure shown in Formula II above.

[0093] In some embodiments, the pharmaceutical composition comprises 35-70% by weight of a water-soluble organic solvent, such as 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, or 70% by weight; preferably, the pharmaceutical composition comprises 40-70% by weight of a water-soluble organic solvent; more preferably, the pharmaceutical composition comprises 45-65% by weight of a water-soluble organic solvent.

[0094] In some embodiments, the pharmaceutical composition comprises 40-55% by weight of a water-soluble organic solvent.

[0095] In some embodiments, the pharmaceutical composition comprises 45-55% by weight of a water-soluble organic solvent.

[0096] In some embodiments, the pharmaceutical composition comprises 50-65% by weight of a water-soluble organic solvent.

[0097] In some embodiments, the water-soluble organic solvent is selected from DMSO.

[0098] In some embodiments, the water-soluble organic solvent is selected from NMP.

[0099] In some embodiments, the water-soluble organic solvent is selected from DMAc.

[0100] In some embodiments, the water-soluble organic solvent is selected from ethanol.

[0101] In some embodiments, the water-soluble organic solvent is DMSO, and the DMSO content in the pharmaceutical composition of the present invention may be 35-70% by weight, preferably 40-70% by weight, particularly preferably 45-65% by weight, for example 55-65% by weight.

[0102] In some embodiments, the pharmaceutical composition optionally further includes triglycerides, such as triacetylglycerol or tripropionate, or mixtures thereof, in an amount of 5 to 20% by weight, for example 10 to 15% by weight, or 5 to 10% by weight, etc.

[0103] In some embodiments, the pharmaceutical composition optionally further includes an organic acid. Most preferably, organic acids have a molecular weight of less than about 300 Da. Representative organic acids include, for example, fumaric acid, maleic acid, methanesulfonic acid, acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid, benzoic acid, salicylic acid, acetylsalicylic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, or pimelic acid. Maleic acid or methanesulfonic acid is preferred.

[0104] In some embodiments, the pharmaceutical composition provided by the present invention, wherein the burepiperazole or a pharmaceutically acceptable salt thereof, preferably a free base of burepiperazole or its hydrate, is used; the term "pharmaceutically acceptable salt" refers to a salt form of a drug having at least one suitable salifying group that does not cause significant adverse toxicological effects on patients. Pharmaceutically acceptable salts include salts prepared by reacting with inorganic acids, organic acids, or acidic amino acids, depending on the nature of the functional groups in the drug. Pharmaceutically acceptable salts suitable for the present invention include acid addition salts, such as salts of burepiperazole formed with hydrochloric acid, phosphoric acid, malic acid, tartaric acid, oxalic acid, succinic acid, hemisuccinic acid, hydrobromic acid, malonic acid, dihydroxynaphthyl acid, etc., which can be prepared by conventional methods, for example, by methods disclosed in the embodiments of CN103781783A, the contents of which are incorporated herein by reference.

[0105] In some embodiments, the pharmaceutical composition provided by the present invention comprises biriperazole or a pharmaceutically acceptable salt thereof being present in a form with a particle size D (90) of not more than 30 μm and not less than 1 μm, or biriperazole or a pharmaceutically acceptable salt thereof being present in a form with a particle size D (90) of not more than 25 μm, or not more than 20 μm, or not more than 15 μm, or not more than 10 μm, or not more than 9 μm, or not more than 8 μm, or not more than 7 μm, or not more than 6 μm, or not more than 5 μm, or not more than 4 μm, or not more than 3 μm, or not more than 2 μm and not less than It exists in the form of 1 μm, for example, the buripiperazole or its pharmaceutically acceptable salts with a particle size D (90) of 1~30 μm, or 1~25 μm, or 2~25 μm, or 2~20 μm, or 2~17 μm, or 2~15 μm, or 2~10 μm, or 2~7 μm, or 2~5 μm, or 3~20 μm, or 3~17 μm, or 3~15 μm, or 3~10 μm, or 3~7 μm, or 3~5 μm, or 5~25 μm, or 5~20 μm, or 5~17 μm, or 5~10 μm, etc.

[0106] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 30 μm and not less than 2 μm.

[0107] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 25 μm and not less than 2 μm.

[0108] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 20 μm and not less than 2 μm.

[0109] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 15 μm and not less than 2 μm.

[0110] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 10 μm and not less than 2 μm.

[0111] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 9 μm and not less than 2 μm.

[0112] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 8 μm and not less than 2 μm.

[0113] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 7 μm and not less than 2 μm.

[0114] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 6 μm and not less than 2 μm.

[0115] In some embodiments, the pharmaceutical composition provided by the present invention contains buripiperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 5 μm and not less than 2 μm.

[0116] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 4 μm and not less than 2 μm.

[0117] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 3 μm and not less than 2 μm.

[0118] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 25 μm and not less than 3 μm.

[0119] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 20 μm and not less than 3 μm.

[0120] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 25 μm and not less than 5 μm.

[0121] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 20 μm and not less than 5 μm.

[0122] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 15 μm and not less than 5 μm.

[0123] In some embodiments, the pharmaceutical composition provided by the present invention contains buriperazole or a pharmaceutically acceptable salt thereof in a form with a particle size D (90) of not more than 5 and not less than 2 μm.

[0124] In some preferred embodiments, the present invention provides an injectable pharmaceutical composition comprising: (a) 10-35% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-45% by weight of a biodegradable copolymer, wherein the biodegradable copolymer comprises at least one of a diblock copolymer or a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 200-50000 Da, and the diblock copolymer comprises 30-95% by weight, preferably 30-91% by weight of polylactic acid; and the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 200-50000 Da, and the triblock copolymer comprises 50-95% by weight, preferably 50-91% by weight of polylactic acid; (c) 40-70% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0125] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 15-35% by weight of a biodegradable copolymer, wherein the biodegradable copolymer comprises at least one of a diblock copolymer or a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-50000 Da, and the diblock copolymer comprises 30-90% by weight of polylactic acid; and the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 400-50000 Da, and the triblock copolymer comprises 50-91% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0126] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-30% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-50000 Da, and the diblock copolymer contains 30-91% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 400-50000 Da, and the triblock copolymer contains 50-91% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0127] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-30% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-25000 Da, and the diblock copolymer contains 30-91% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 400-30000 Da, and the triblock copolymer contains 50-95% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0128] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-25% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-10000 Da, and the diblock copolymer contains 30-91% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 400-10000 Da, and the triblock copolymer contains 50-91% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0129] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-20% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-10000 Da, and the diblock copolymer contains 30-91% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 400-10000 Da, and the triblock copolymer contains 50-91% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0130] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-20% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 200-1500 Da, and the diblock copolymer contains 30-80% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 200-4500 Da, and the triblock copolymer contains 50-80% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0131] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 15-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-20% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-800 Da, and the diblock copolymer contains 30-80% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-800 Da, and the triblock copolymer contains 50-80% by weight of polylactic acid; (c) 40-65% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0132] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 5-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-20% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-800 Da, and the diblock copolymer contains 30-80% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-800 Da, and the triblock copolymer contains 50-80% by weight of polylactic acid; (c) 35-80% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably the water-soluble organic solvent is DMSO.

[0133] More preferably, in the above pharmaceutical composition, one segment of the polyethylene glycol chain in the diblock polymer is methyl-terminated, i.e., mPEG.

[0134] More preferably, the above-mentioned pharmaceutical composition contains buriperazole, or its hydrochloride, or its pamoate.

[0135] More preferably, the particle size distribution of the above-mentioned pharmaceutical composition, wherein burepiperazole or its pharmaceutically acceptable salt has the following characteristics: D(90) is from 1 μm to 30 μm, for example, D(90) is 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm or 30 μm, and any two of these values. Preferably, D(90) is in the range of 1μm to 25μm, or 2μm to 25μm, or 3μm to 25μm, or 4μm to 25μm, or 5μm to 25μm, or 1μm to 20μm, or 2μm to 20μm, or 3μm to 20μm, or 4μm to 20μm, or 5μm to 20μm, or 2μm to 15μm, or 5μm to 15μm, or 2μm to 17μm, or 2μm to 10μm, or 2μm to 5μm, etc.

[0136] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 5-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-25% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-1000 Da, and the diblock copolymer contains 30-80% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 300-1000 Da, and the triblock copolymer contains 50-80% by weight of polylactic acid; (c) 35-80% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one selected from DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably, the water-soluble organic solvent is DMSO; The particle size D(90) of buripiperazole or its pharmaceutically acceptable salt is preferably 2-20 μm, more preferably 5-20 μm, or 2-10 μm, or 2-5 μm.

[0137] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 5-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-25% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 1000-1500 Da, and the diblock copolymer contains 70-80% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 1000-4500 Da, and the triblock copolymer contains 70-80% by weight of polylactic acid; (c) 35-80% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one selected from DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably, the water-soluble organic solvent is DMSO; The particle size D(90) of buripiperazole or its pharmaceutically acceptable salt is preferably 2-20 μm, more preferably 5-20 μm, or 2-10 μm, or 2-5 μm.

[0138] In a preferred embodiment, the present invention provides a pharmaceutical composition for injection, comprising: (a) 5-30% by weight of biriperazole or a pharmaceutically acceptable salt thereof; (b) 10-25% by weight of a diblock copolymer and 5-15% by weight of a triblock copolymer; wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 1500-22000 Da, and the diblock copolymer contains 75-95% by weight of polylactic acid; the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 4500-22000 Da, and the triblock copolymer contains 75-95% by weight of polylactic acid; (c) 35-80% by weight of a water-soluble organic solvent, wherein the water-soluble organic solvent is at least one selected from DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, benzyl alcohol or isopropanol; preferably, the water-soluble organic solvent is DMSO; The particle size D(90) of buripiperazole or its pharmaceutically acceptable salt is preferably 10-30 μm, more preferably 10-25 μm, or 15-20 μm, or 2-5 μm.

[0139] In another aspect, the present invention provides a pharmaceutical formulation, wherein a unit dose of the pharmaceutical formulation comprises: (a) 50-900 mg of ibuprofen, or an equimolar amount of its pharmaceutically acceptable salt; (b) 50 to 500 mg of a biodegradable copolymer, wherein the biodegradable copolymer comprises at least one of a diblock copolymer or a triblock copolymer; The diblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 200-1500 Da, preferably 300-1500, and the diblock polymer contains 30-95% by weight of polylactic acid, preferably 30-80% by weight of polylactic acid. The triblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 200-4500 Da, preferably 300-1500, and the triblock polymer contains 30-95% by weight of polylactic acid, preferably 50-80% by weight of polylactic acid. (c) 100~300 mg of a water-soluble organic solvent, wherein the water-soluble organic solvent is selected from DMSO, NMP, DMAC, ethanol or a combination thereof; Preferably, the particle size D(90) of buripiperazole or its pharmaceutically acceptable salt is 2-20 μm, more preferably 2-17 μm, or 2-10 μm, or 2-5 μm.

[0140] More preferably, the pharmaceutical preparation contains 50-400 mg of biriperazole or a pharmaceutically acceptable salt thereof per unit dose, for example, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg or 400 mg of biriperazole or a pharmaceutically acceptable salt thereof; preferably, the pharmaceutical preparation contains 50-300 mg of biriperazole or a pharmaceutically acceptable salt thereof per unit dose.

[0141] In some embodiments, the pharmaceutical preparation contains 50 mg of birepiperazole per unit dose.

[0142] In some embodiments, the pharmaceutical preparation contains 75 mg of birepiperazole per unit dose.

[0143] In some embodiments, the pharmaceutical preparation contains 89 mg of burepiperazole per unit dose.

[0144] In some embodiments, the pharmaceutical preparation contains 100 mg of birepiperazole per unit dose.

[0145] In some embodiments, the pharmaceutical preparation contains 120 mg of birepiperazole per unit dose.

[0146] In some embodiments, the pharmaceutical preparation contains 150 mg of birepiperazole per unit dose.

[0147] In some embodiments, the pharmaceutical preparation contains 200 mg of birepiperazole per unit dose.

[0148] In some embodiments, the pharmaceutical preparation comprises 250 mg of birepiperazole per unit dose.

[0149] In some embodiments, the pharmaceutical preparation contains 300 mg of birepiperazole per unit dose.

[0150] In some embodiments, the pharmaceutical preparation contains 350 mg of birepiperazole per unit dose.

[0151] In some embodiments, the pharmaceutical preparation contains 400 mg of burepiperazole per unit dose.

[0152] In some embodiments, the pharmaceutical formulation comprises 50-300 mg of biodegradable copolymer per unit dose, for example, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg or 300 mg of biodegradable copolymer, preferably 50-200 mg or 50-100 mg of biodegradable copolymer.

[0153] In some embodiments, the unit dose of the pharmaceutical formulation comprises 50-200 mg of diblock copolymer, for example, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg of diblock copolymer, preferably the unit dose of the pharmaceutical formulation comprises 50-100 mg of diblock copolymer.

[0154] In some embodiments, the unit dose of the pharmaceutical formulation comprises 0-100 mg of triblock copolymer, for example, 0 mg, 10 mg, 20 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of triblock copolymer, preferably the unit dose of the pharmaceutical formulation comprises 0-50 mg of triblock copolymer.

[0155] In some embodiments, the unit dose of the pharmaceutical preparation contains 50-200 mg of water-soluble organic solvent; for example, it contains 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg of water-soluble organic solvent. Preferably, the unit dose of the pharmaceutical preparation contains 100-200 mg of water-soluble organic solvent. More preferably, the water-soluble organic solvent is DMSO.

[0156] In a preferred embodiment, a pharmaceutical preparation is provided, wherein a unit dose of the pharmaceutical preparation comprises: (a) 50-200 mg of ibuprofen, or an equimolar amount of its pharmaceutically acceptable salt; (b) 50-200 mg of diblock copolymer and 0-100 mg of triblock copolymer; The diblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 300-10000 Da, preferably 300-1500 Da, and the diblock polymer contains 30-80% by weight of polylactic acid; The triblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 400-10000 Da, preferably 300-1500 Da, and the triblock polymer contains 50-80% by weight of polylactic acid. (c) 100~200 mg of water-soluble organic solvent, wherein the water-soluble organic solvent is selected from DMSO, NMP, DMAC, ethanol or a combination thereof, preferably DMSO; In a preferred embodiment, a pharmaceutical preparation is provided, wherein a unit dose of the pharmaceutical preparation comprises: (a) 50-200 mg of ibuprofen, or an equimolar amount of its pharmaceutically acceptable salt; (b) 50-200 mg of diblock copolymer and 0-100 mg of triblock copolymer; The diblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 100-1500 Da, preferably 300-1500 Da, and the diblock polymer contains 30-80% by weight of polylactic acid. The triblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 100-1500 Da, preferably 300-1500 Da, and the triblock polymer contains 50-80% by weight of polylactic acid. (c) 100~200 mg of water-soluble organic solvent, wherein the water-soluble organic solvent is selected from DMSO, NMP, DMAC, ethanol or a combination thereof, preferably DMSO; Further preferably, in the pharmaceutical formulation, wherein the diblock copolymer and triblock copolymer are as described above, the particle size of the birepiperazole or its pharmaceutically acceptable salt is: D(90) in the range of 1 μm to 30 μm, preferably in the range of 1 μm to 25 μm, or in the range of 2 μm to 25 μm, or in the range of 1 μm to 20 μm, or in the range of 3 μm to 25 μm, or in the range of 3 μm to 20 μm, or in the range of 3 μm to 30 μm, or in the range of 5 μm to 25 μm, or in the range of 5 μm to 20 μm, or in the range of 1 μm to 15 μm, or in the range of 1 μm to 10 μm, or in the range of 1 μm to 5 μm, or in the range of 2 μm to 20 μm, or in the range of 2 μm to 17 μm, or in the range of 2 μm to 10 μm, or in the range of 2 μm to 5 μm, etc.

[0157] A third aspect of the invention also provides the use of the pharmaceutical composition and the pharmaceutical preparation in the preparation of a medicament for treating and / or preventing diseases of the central nervous system.

[0158] Preferably, the central nervous system disease is selected from one or more of the following: schizophrenia, bipolar disorder, mental disorder, mania, depression, anxiety disorder, sleep disorder, delirium, cognitive impairment, cognitive impairment associated with Alzheimer's disease, Parkinson's disease or dementia behavior and mental symptoms caused by cognitive impairment; Further preferably, the central nervous system disease is selected from schizophrenia, bipolar disorder, or depression.

[0159] In a fourth aspect, the present invention also provides a method for preparing the pharmaceutical composition and the pharmaceutical formulation, the method comprising: adding a water-soluble organic solvent and a biodegradable copolymer to birepiperazole or a pharmaceutically acceptable salt thereof; more specifically, the method comprises: adding a prescribed amount of a biodegradable copolymer (such as a diblock copolymer and a triblock copolymer) to a water-soluble organic solvent (such as DMSO), stirring until the biodegradable copolymer is completely dissolved, and then adding a prescribed amount of birepiperazole or a pharmaceutically acceptable salt thereof, stirring to dissolve the birepiperazole or the pharmaceutically acceptable salt thereof, thereby obtaining the pharmaceutical composition.

[0160] In another aspect, the present invention provides a method for administering biriperazole or a pharmaceutically acceptable salt thereof to a patient, the method comprising administering the pharmaceutical composition provided by the present invention to the patient parenterally; more preferably, the method comprises administering the pharmaceutical composition provided by the present invention to the patient intramuscularly, intraperitoneally, intraperitoneally, subcutaneously, intravenously, or intra-arterially; particularly preferably, the method comprises subcutaneously injecting the pharmaceutical composition provided by the present invention into the patient.

[0161] In some embodiments, the present invention provides a method for treating a disease or disorder (i.e., schizophrenia, bipolar disorder, or depression, etc.) in patients in need, wherein the method comprises subcutaneously administering the pharmaceutical composition disclosed herein to the patient.

[0162] In some implementations, tolerability is determined by oral ibuprofen treatment before starting subcutaneous injection therapy.

[0163] In some embodiments, the method includes subcutaneously injecting the pharmaceutical composition provided by the present invention into a patient. In these respects, the subcutaneous injection can be performed at any suitable site on the patient's body. In some embodiments, the subcutaneous injection is performed in the patient's abdomen. In other embodiments, the subcutaneous injection is performed in the patient's upper arm. In other embodiments, the subcutaneous injection is performed in the patient's thigh. In other embodiments, the subcutaneous injection is performed in the patient's back.

[0164] In some embodiments, the subcutaneously administered pharmaceutical composition contains 50 to 000 mg, preferably 50 to 300 mg, of biriperazole, for example, containing 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, or 300 mg of biriperazole.

[0165] In some embodiments, the subcutaneously administered pharmaceutical composition contains 50 mg of burepiperazole.

[0166] In some embodiments, the subcutaneously administered pharmaceutical composition contains 75 mg of birepiperazole.

[0167] In some embodiments, the subcutaneously administered pharmaceutical composition contains 89 mg of burepiperazole.

[0168] In some embodiments, the subcutaneously administered pharmaceutical composition contains 100 mg of birepiperazole.

[0169] In some embodiments, the subcutaneously administered pharmaceutical composition contains 120 mg of birepiperazole.

[0170] In some embodiments, the subcutaneously administered pharmaceutical composition contains 150 mg of birepiperazole.

[0171] In some embodiments, the subcutaneously administered pharmaceutical composition contains 200 mg of birepiperazole.

[0172] In some embodiments, the subcutaneously administered pharmaceutical composition contains 250 mg of birepiperazole.

[0173] In some embodiments, the subcutaneously administered pharmaceutical composition contains 300 mg of biriperazole.

[0174] In some embodiments, the subcutaneously administered pharmaceutical composition contains 350 mg of biriperazole.

[0175] In some embodiments, the subcutaneously administered pharmaceutical composition contains 400 mg of burepiperazole.

[0176] The pharmaceutical composition provided by this invention has a high drug loading capacity; for example, even with a drug loading capacity as high as 30% by weight, there is no problem of biriperazole precipitating from the pharmaceutical composition. This is beneficial for reducing the volume of a single administration, thereby reducing administration irritation or discomfort caused by excessive administration volume. Therefore, in some aspects of the disclosed treatment methods, the volume of a single subcutaneous administration of the pharmaceutical composition described in this invention is about 0.1 mL to 2.0 mL, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, or about 2.0 mL, preferably about 0.5 mL to 2.0 mL, and particularly preferably 0.5 mL to 1.0 mL.

[0177] In some embodiments, upon subcutaneous injection of the pharmaceutical composition provided by the present invention, the organic solvent diffuses while the block copolymer (insoluble in an aqueous medium) precipitates, thereby forming a reservoir encapsulating birepiperazole. Birepiperazole is slowly released from the reservoir through drug diffusion and / or gradual reservoir degradation to achieve and maintain therapeutic levels of the drug over a period of time. In some embodiments, the time period is 28 days ± 5 days, for example, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, or 31 days. In some embodiments, the time period is 30 days or about 30 days. In some embodiments, the time period is 60 days or about 60 days.

[0178] In some embodiments, the pharmaceutical composition provided by the present invention is administered subcutaneously once a month. In other embodiments, the birepiperazole pharmaceutical composition provided by the present invention is administered once every two months.

[0179] In some embodiments, the pharmaceutical composition provided by the present invention is administered once a month or once every two months, and buriperazole is continuously released in the body and maintains an effective blood concentration.

[0180] The sixth aspect of the present invention provides a biodegradable copolymer comprising a diblock copolymer and a triblock copolymer, wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 200-1500 Da; and the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number average molecular weight of 200-4500 Da. Preferably, the number-average molecular weight of the diblock copolymer is 300-1500 Da, and the number-average molecular weight of the triblock copolymer is 300-1200 Da. Further preferably, the number-average molecular weight of the diblock copolymer is 300~1000 Da; the number-average molecular weight of the triblock copolymer is 300~1000 Da.

[0181] Further preferably, the number-average molecular weight of the diblock copolymer is 300-800 Da; the number-average molecular weight of the triblock copolymer is 300-800 Da.

[0182] Further preferably, the biodegradable copolymer contains 30-95% by weight of polylactic acid, more preferably 30-80% by weight of polylactic acid; Further preferably, the terminal hydroxyl groups at one end of the polyethylene glycol chain in the diblock copolymer are C 1~3 The alkyl end is capped, and the terminal hydroxyl group at the other end forms an ester bond with the polylactic acid chain.

[0183] Further preferably, the biodegradable copolymer, wherein the triblock copolymer contains 40-95% by weight of polylactic acid, more preferably 50-80% by weight of polylactic acid; Further preferably, the triblock copolymer is obtained by forming ester bonds between the terminal hydroxyl groups at both ends of the polyethylene glycol chain and the polylactic acid chain.

[0184] In some preferred embodiments, the biodegradable copolymers include diblock copolymers having a number-average molecular weight of about 200 Da to 1500 Da and containing 30 to 80% by weight of polylactic acid; and triblock copolymers having a number-average molecular weight of 200 to 4500 Da and containing 50 to 80% by weight of polylactic acid.

[0185] In some preferred embodiments, the biodegradable copolymers include diblock copolymers having a number-average molecular weight of about 200 Da to 1500 Da and containing 30 to 80% by weight of polylactic acid; and triblock copolymers having a number-average molecular weight of 200 to 1500 Da and containing 50 to 80% by weight of polylactic acid.

[0186] In some preferred embodiments, the biodegradable copolymers include diblock copolymers having a number average molecular weight of about 200 Da to 1000 Da and containing 30 to 80% by weight of polylactic acid; and triblock copolymers having a number average molecular weight of 200 to 1000 Da and containing 50 to 80% by weight of polylactic acid.

[0187] In some preferred embodiments, the biodegradable copolymers include diblock copolymers having a number average molecular weight of about 300 Da to 1500 Da and containing 30 to 80% by weight of polylactic acid; and triblock copolymers having a number average molecular weight of 300 to 1500 Da and containing 50 to 80% by weight of polylactic acid.

[0188] In some preferred embodiments, the biodegradable copolymers include diblock copolymers having a number average molecular weight of about 300 Da to 800 Da and containing 30 to 80% by weight of polylactic acid; and triblock copolymers having a number average molecular weight of 300 to 800 Da and containing 50 to 80% by weight of polylactic acid.

[0189] In some preferred embodiments, the biodegradable copolymers include diblock copolymers having a number average molecular weight of about 300 Da to 600 Da and containing 30 to 80% by weight of polylactic acid; and triblock copolymers having a number average molecular weight of 300 to 800 Da and containing 50 to 80% by weight of polylactic acid.

[0190] In some preferred embodiments, the biodegradable copolymers are wherein the number-average molecular weight of polyethylene glycol in the diblock copolymer is about 100-2000 Da and the number-average molecular weight of polylactic acid is about 100-2000 Da; and the number-average molecular weight of polyethylene glycol in the triblock copolymer is about 100-2000 Da and the number-average molecular weight of polylactic acid is about 100-3500 Da.

[0191] In some preferred embodiments, the biodegradable copolymers are wherein the number-average molecular weight of polyethylene glycol in the diblock copolymer is about 100-500 Da and the number-average molecular weight of polylactic acid is about 100-1200 Da; and the number-average molecular weight of polyethylene glycol in the triblock copolymer is about 100-1000 Da and the number-average molecular weight of polylactic acid is about 100-3500 Da.

[0192] In some preferred embodiments, the biodegradable copolymers are wherein the number-average molecular weight of polyethylene glycol in the diblock copolymer is about 100-500 Da and the number-average molecular weight of polylactic acid is about 100-1200 Da; and the number-average molecular weight of polyethylene glycol in the triblock copolymer is about 100-1000 Da and the number-average molecular weight of polylactic acid is about 100-1500 Da.

[0193] In some preferred embodiments, the biodegradable copolymers are wherein the number-average molecular weight of polyethylene glycol in the diblock copolymer is about 100-500 Da and the number-average molecular weight of polylactic acid is about 100-1000 Da; and the number-average molecular weight of polyethylene glycol in the triblock copolymer is about 100-500 Da and the number-average molecular weight of polylactic acid is about 100-1000 Da.

[0194] In some preferred embodiments, the biodegradable copolymers are wherein the diblock copolymers have a polyethylene glycol number-average molecular weight of about 200 Da and polylactic acid number-average molecular weight of about 100 to 600 Da; and the triblock copolymers have a polyethylene glycol number-average molecular weight of about 200 Da and polylactic acid number-average molecular weight of about 200 to 600 Da.

[0195] In some preferred embodiments, the biodegradable copolymer is wherein the diblock copolymer is mPEG-PLA, wherein the mPEG molecular weight is 350 Da and the PLA molecular weight is 1150 Da; and the triblock copolymer is PLA-PEG-PLA, wherein the polyethylene glycol number-average molecular weight is 1000 Da and the polylactic acid number-average molecular weight is 3000~3500 Da.

[0196] In some preferred embodiments, the biodegradable copolymer is wherein the diblock copolymer is mPEG-PLA, wherein the mPEG molecular weight of the diblock copolymer is 200 Da and the PLA molecular weight is 100 Da; and the triblock copolymer is PLA-PEG-PLA, wherein the number-average molecular weight of polyethylene glycol in the triblock copolymer is 200 Da and the number-average molecular weight of polylactic acid is 100-200 Da.

[0197] In some preferred embodiments, the biodegradable copolymer is wherein the diblock copolymer is mPEG-PLA, wherein the mPEG molecular weight of the diblock copolymer is 200 Da and the PLA molecular weight is 600 Da; and the triblock copolymer is PLA-PEG-PLA, wherein the number-average molecular weight of polyethylene glycol in the triblock copolymer is 200 Da and the number-average molecular weight of polylactic acid is 300-600 Da.

[0198] More preferably, the biodegradable copolymers, wherein the diblock copolymers and triblock copolymers have the structures shown in Formula I and Formula II, respectively.

[0199] Further preferably, the biodegradable copolymer is wherein the weight ratio of the diblock copolymer to the triblock copolymer is (10~45):(5~15), preferably (10~25):(5~15), more preferably (15~25):(5~15), or (15~25):(10~15). In another embodiment, a pharmaceutical composition comprising the aforementioned biodegradable copolymer is provided, the pharmaceutical composition further comprising at least one pharmaceutically active ingredient and a water-soluble organic solvent; The active pharmaceutical ingredient is selected from bripiprazole, aripiprazole, risperidone, paliperidone, paliperidone palmitate, haloperidol, clozapine, olanzapine, buspirone, giperone, quetiapine, amisulpride, palapirone, bubenazine, and ziprasidone, or pharmaceutically acceptable salts thereof; preferably, the active pharmaceutical ingredient is selected from bripiprazole, aripiprazole, risperidone, paliperidone palmitate, or pharmaceutically acceptable salts thereof; The water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol or isopropanol; More preferably, the content of the active pharmaceutical ingredient in the pharmaceutical composition is 5-35% by weight, based on the total amount of the pharmaceutical composition. Further preferably, the particle size distribution D90 of the active pharmaceutical ingredient is 2~25 μm. Even more preferably, the active pharmaceutical ingredient is ibuprofen or a pharmaceutically acceptable salt; More preferably, the content of water-soluble organic solvent in the pharmaceutical composition is 35-80% by weight, based on the total amount of the pharmaceutical composition. More preferably, based on the total amount of the pharmaceutical composition, the content of the diblock copolymer in the pharmaceutical composition is 10-45% by weight, preferably 10-25% by weight, and the content of the triblock copolymer is preferably 5-15% by weight; A seventh aspect of the present invention provides the use of the aforementioned biodegradable copolymer and / or pharmaceutical composition in the preparation of a medicament for treating and / or preventing central nervous system diseases; preferably, the biodegradable copolymer is added to a water-soluble organic solvent and a pharmaceutical active ingredient to prepare a biodegradable drug delivery composition.

[0200] The neuropsychiatric disorders mentioned herein are selected from one or more of the following: schizophrenia, bipolar disorder, mental disorders, mania, depression, anxiety disorders, sleep disorders, delirium, cognitive impairment, cognitive impairment associated with Alzheimer's disease, Parkinson's disease or dementia behaviors and mental symptoms caused by cognitive impairment; preferably, the neuropsychiatric disorders mentioned herein are selected from any one or more of the following: schizophrenia, depression, bipolar disorder, mental disorders, mania, depression, and more preferably schizophrenia.

[0201] The drugs mentioned include, but are not limited to, buriperazole, aripiprazole, risperidone, paliperidone, or their pharmaceutically acceptable salts.

[0202] Preferably, the particle size distribution of the active pharmaceutical ingredient is: D(90) in the range of 1 μm to 30 μm, preferably in the range of 1 μm to 25 μm, or in the range of 2 μm to 25 μm, or in the range of 1 μm to 20 μm, or in the range of 3 μm to 25 μm, or in the range of 3 μm to 20 μm, or in the range of 3 μm to 30 μm, or in the range of 5 μm to 25 μm, or in the range of 5 μm to 20 μm, or in the range of 5 μm to 10 μm, or in the range of 1 μm to 15 μm, or in the range of 1 μm to 10 μm, or in the range of 1 μm to 5 μm, or in the range of 2 μm to 20 μm, or in the range of 2 μm to 17 μm, or in the range of 2 μm to 10 μm, or in the range of 2 μm to 5 μm, etc.

[0203] More preferably, the biodegradable drug delivery composition contains 5-35% by weight of the active pharmaceutical ingredient, 10-45% by weight of the biodegradable copolymer, and 35-80% by weight of the water-soluble organic solvent.

[0204] More preferably, in the biodegradable drug delivery composition, the diblock copolymer content is 10-45% by weight, preferably 10-25% by weight; and the triblock copolymer content is 5-15% by weight.

[0205] In an eighth aspect of the invention, a method for preparing the biodegradable copolymer is also provided, comprising: reacting polyethylene glycol and lactide in an organic solvent in the presence of a catalyst to obtain a diblock copolymer; and reacting polyethylene glycol and lactide in an organic solvent in the presence of a catalyst to obtain a triblock copolymer.

[0206] More preferably, the target molecular weight mPEG is added to an organic solvent, followed by the addition of the target polymerization amount of D,L-lactide and a catalyst, and the reaction is heated to obtain a diblock copolymer. More preferably, PEG of the target molecular weight is added to an organic solvent, followed by D,L-lactide of the target polymerization degree and a catalyst, and the mixture is heated to react and separate to obtain a triblock copolymer.

[0207] Preferably, the organic solvent includes, but is not limited to: ethanol, isopropanol, ethyl acetate, THF, toluene, or dichloromethane.

[0208] Preferably, the catalyst is selected from stannous octoate, zinc lactate, or zinc octoate, etc.

[0209] Preferably, the heating temperature is the reflux temperature.

[0210] Technical effect This invention provides a novel long-acting injectable birepiperazole pharmaceutical composition. The pharmaceutical composition is obtained by optimizing the molecular weight, monomer composition, and ratio of the copolymer to the active ingredient of the biodegradable copolymer. This composition exhibits good in vivo pharmacokinetic effects, increasing the exposure of birepiperazole in vivo, reducing the peak-to-trough ratio of birepiperazole blood concentration, and simultaneously providing sustained and stable release over a long period while maintaining effective blood concentrations. For example, the sustained release time in vivo reaches approximately 30 days, allowing for once-monthly dosing. This significantly improves drug utilization efficiency, therapeutic efficacy, and patient compliance.

[0211] Furthermore, the pharmaceutical composition provided by this invention exhibits a small peak-to-trough ratio, stable blood drug concentration, and minimal adverse reactions during in vivo release. After subcutaneous injection, biriperazole is released more rapidly in the early stages, reducing or avoiding the need for additional oral preparations after subcutaneous injection, making it simpler and more convenient to use.

[0212] The pharmaceutical composition provided by this invention uses a low molecular weight diblock and triblock biodegradable copolymer containing polyethylene glycol and polylactic acid and a specific particle size (D90) of active pharmaceutical ingredient. After the first peak and trough, the drug begins to be released continuously and steadily, with the efficacy lasting for 28±5 days, preferably 28±3 days, and more preferably 28±2 days. During the study, extremely high levels of irinotecan were maintained, and more than 80% of the drug was basically released within 28±5 days, effectively reducing the drug's retention in the storage and improving drug safety.

[0213] Because buripiperazole has low solubility, a high drug loading can lead to drug precipitation in the formulation, affecting drug stability and thus posing risks to safety and efficacy. The pharmaceutical composition provided by this invention, by optimizing the biodegradable copolymers in the drug carrier system as well as the type and amount of solvent, can achieve a high drug loading in the pharmaceutical composition, such as up to 30% by weight, preferably 5-30% by weight, without causing drug (such as buripiperazole) precipitation problems. Stability studies show that when placed at 2-8°C for more than three months (e.g., 113 days), the particle size of the active ingredient in the pharmaceutical composition remains essentially unchanged, and no drug precipitation occurs.

[0214] Another advantage of increasing drug loading is that when administering the same dose of drug, the injection volume of the formulation can be significantly reduced, which helps to improve medication adherence.

[0215] Terminology Definition This invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials described herein can be used to practice this invention. This invention is by no means limited to the methods and materials described herein.

[0216] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0217] All patents and publications involved in this invention are incorporated herein by reference in their entirety.

[0218] As used herein, the term "biodegradable" refers to the degradation, breakdown, or digestion of polymers through biological and environmental processes, including those of living organisms, particularly at physiological pH and temperature. For example, triblock and diblock copolymers undergo hydrolysis of the bonds between and within the copolymer units over time in vivo, forming smaller, non-toxic components.

[0219] In the context of this invention, "molecular weight" refers to the nominal average molecular weight of a polymer (such as biodegradable copolymers, polyethylene glycol, polylactic acid), typically determined using GPC (gel permeation chromatography) or NMR (nuclear magnetic resonance). Molecular weight can be expressed as number-average molecular weight or weight-average molecular weight. Unless otherwise indicated, all molecular weights mentioned herein are number-average molecular weights. Both number-average and weight-average molecular weights can be determined using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values ​​can also be used, such as the end-group integration method of NMR to determine the true number-average molecular weight of the polymer when precise control of the degree of polymerization is required; or the weight-average molecular weight can be determined using light scattering techniques, ultracentrifugation, or viscometry.

[0220] It should be noted that certain properties of polymers, such as molecular weight, molecular number, number of repeating units of monomers, etc., are usually described as discrete values ​​in this document. However, those skilled in the art should understand that due to the complex nature of copolymers, such values ​​usually refer to average values.

[0221] The term "theoretical molecular weight" refers to the molecular weight of a copolymer determined by calculating the sum of the molar amounts of the repeating units that make up the polymer. The theoretical molecular weight indicates the average length of the target polymer chain.

[0222] The term "parenteral administration" includes intramuscular, intraperitoneal, intraperitoneal, subcutaneous, intravenous, and intraarterial administration. It also includes intradermal, intracavernosal, intravitreal, intracerebral, intrathecal, epidural, and intraosseous administration. In some embodiments, the formulations disclosed herein are administered subcutaneously. In specific embodiments, the birepiperazole pharmaceutical compositions disclosed herein are administered subcutaneously by a healthcare professional. Subcutaneous injection can be performed at any suitable site on the skin of the subject to whom the composition is administered. Exemplary sites include the abdomen, arm, small part of the back, thigh, etc.

[0223] The pharmaceutical composition or biodegradable drug delivery composition may be an injectable liquid at room temperature and can be injected with a syringe without excessive force. The pharmaceutical composition or biodegradable drug delivery composition is also formed in situ and biodegradable, and becomes a solid implant or depot when injected into an animal or patient.

[0224] The active ingredient according to the present invention, namely the active pharmaceutical ingredient (API), is birepiperazole and its pharmaceutically acceptable salt.

[0225] The terms “selected from…”, “preferred…”, and “more preferred…” refer to one or more elements from the group listed below, selected independently, and may include combinations of two or more elements. In this invention, one element from the group listed below is preferred. As used herein, “brevipiprazole formulation,” “long-acting injectable birepiprazole formulation,” “brevipiprazole pharmaceutical composition,” “pharmaceutical composition,” and “pharmaceutical formulation” refer to the birepiprazole pharmaceutical composition described herein and may be used interchangeably.

[0226] As used herein, the terms “once a month” or “once every month” mean once a month and are used interchangeably. In some implementations, “once a month” or “q1m” or “Q1M” or “once every month” means once every 4 weeks (Q4W) or once every 28–31 days, for example, once every 28 days, once every 29 days, once every 30 days, or once every 31 days.

[0227] As used herein, the terms “once every two months” or “q2m” or “Q2M” mean once every 8 weeks (Q8W), or once every 56–62 days, for example, once every 56 days, once every 57 days, once every 58 days, once every 59 days, once every 60 days, once every 61 days, or once every 62 days.

[0228] In a preferred embodiment, the pharmaceutical composition is administered subcutaneously once a month. Therefore, a treatment regimen using the pharmaceutical composition provided by this invention comprises a series of monthly subcutaneous injections. Each monthly subcutaneous injection has associated pharmacokinetic parameters, such as the maximum plasma concentration of birepiperazole (C2). max ), T max AUC, etc. In some aspects of the disclosed treatment methods, patients reach a steady state where there are no significant changes in the pharmacokinetic parameters of birepiperazole during consecutive monthly subcutaneous injections. In some embodiments, steady state is reached between the first and second monthly subcutaneous injections. In other embodiments, steady state is reached between the second and third monthly subcutaneous injections.

[0229] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0230] In the context of this invention, all figures disclosed herein are approximate values, regardless of whether words such as “about,” “approximately,” or “roughly” are used. Each figure may vary by less than 10% or by a difference that is considered reasonable by those skilled in the art, such as 1%, 2%, 3%, 4%, or 5%. Where numerical ranges are provided, it should be understood that the upper and lower limits of the range, as well as every intermediate value between the upper and lower limits, are included in this disclosure.

[0231] "Treatment" or "prevention" of a disease or condition includes preventing the onset of disease (preventive treatment), suppressing disease (slowing or halting its development), providing relief from the symptoms or side effects of disease (including mitigation treatment), and alleviating disease (causing disease remission) in animals that may be predisposed to the disease but have not yet experienced or presented symptoms of the disease.

[0232] The term "patient" or "patient" is used throughout this specification to describe a person receiving treatment (including prophylactic treatment) with the compositions provided in this disclosure. As used herein, the term "patient" or "patient" also refers to a single human being, or, where the context permits, a group of humans. Thus, in some embodiments, a patient is an individual human being. In other embodiments, a patient is a group of humans.

[0233] In the context of this invention, "unit dose," "single dose," or "unit dosage" has the conventional meaning in the art, referring to the smallest unit of administration, the smallest unit of payment, or the smallest unit of packaging that can be divided in a drug, such as a tablet (unit dosage), a capsule (unit dosage), or an injection (unit dosage), etc.

[0234] The term "water-soluble organic solvent" as used in this article refers to organic solvents that are miscible with water, such as DMSO, DMF, NMP, DMAC, or ethanol.

[0235] The term "repeating unit" refers to the basic repeating unit of a polymer, such as lactic acid (LA), which is the repeating unit of polylactic acid, and ethylene oxide (EO), which is the repeating unit of polyethylene glycol.

[0236] The abbreviation "PEG" refers to poly(ethylene glycol), poly(ethylene oxide), or poly(ethylene oxide), and the terms are used interchangeably. PEG polymers consist of repeating units of ethylene glycol (also known as ethylene oxide (EO)).

[0237] The abbreviation "PLA" refers to polylactide, polylactic acid, or poly(lactic acid), and these terms are used interchangeably in this document. PLA contains the repeating unit of lactic acid (LA).

[0238] The abbreviation "TB" refers to triblock copolymer, which can also be written as "polylactic acid-polyethylene glycol-polylactic acid", "PLA-PEG-PLA", or "polylactic acid-PEG-polylactic acid". The abbreviation "DB" refers to diblock copolymers, which can also be written as "polyethylene glycol-polylactic acid". The methoxy-terminated PEG diblock copolymer can also be written as "mPEG-PLA".

[0239] "Terminated polyethylene glycol" refers to PEG in which one of its terminal hydroxyl groups reacts, including alkoxy-terminated PEG, urethane-terminated PEG, ester-terminated PEG, and similar compounds. The terminating group is a chemical group that does not contain chemical functional groups that readily react with cyclic esters such as lactide, glycolide, caprolactone, or other esters and mixtures thereof. Termination-terminated PEG polymers react with lactide (or polylactic acid) to form diblock copolymers. For example, mPEG-PLA refers to an alkoxy-terminated PEG-polylactic acid diblock copolymer.

[0240] As used herein, the term "diblock" refers to a copolymer of polyethylene glycol and polylactic acid, preferably a methoxylated PEG-polylactic acid copolymer. "mPEG" refers to methoxylated polyethylene glycol. The PEG in the diblock copolymer can be capped with known capping entities other than methoxylated compounds.

[0241] "mpk" is an abbreviation for milligrams per kilogram; AUC 0-t "This refers to the area under the blood drug concentration-time curve from 0:00 to the sampling time point t; “C max "" refers to the maximum plasma concentration.

[0242] “D(90)” indicates that 90% (by volume) of the particles have a diameter less than or equal to the specified value. For example, D(90) of 25 μm means that 90% (by volume) of the particles have a diameter less than or equal to 25 μm. Particle size is typically determined by laser diffraction, using a Malvern Instruments MAZ3000 instrument.

[0243] In this invention context, the particle size D (90) of the irinotecan or its pharmaceutically acceptable salt is specifically described as being determined by a dry method. An exemplary method is as follows: approximately 100 mg of sample is taken and tested using a dry method (Malvern Mastersizer 3000 laser particle size analyzer) according to the instrument parameters described above. Two parallel determinations are performed, with the instrument parameters set as follows: Particle refractive index: 1.646, particle absorptivity: 0.04, density: 1.05 g / cm³ 3 Background measurement time: 10s, sample measurement time: 10s, shading range: 0.5%~6%, injection pressure: 4.0bar, injection rate: 80%, hopper gap: 1.5mm, venturi tube type: standard venturi tube; analysis settings: analysis model - general, fine powder mode. Attached Figure Description

[0244] Figure 1 The graph shows the blood concentration-time curve after subcutaneous injection of long-acting birepiperazole with formulation CF1-5 into rats. from Figure 1 The rat pharmacokinetic (PK) results show that the long-acting birepiperazole injection provided by this invention can continuously release birepiperazole for a relatively long period after administration. The results of tests on formulations CF2 and CF3 indicate that increasing the amount of DB in the biodegradable copolymer has no significant effect on release, suggesting that the ratio between TB and DB copolymers can fluctuate within a wide range, indicating high formulation compatibility. Comparison of the in vivo PK results for formulations CF2 and CF4 shows that a decrease in drug loading leads to a decrease in drug exposure in rats, which is positively correlated with a decrease in the administered dose, proving that the drug loading has no significant effect on release. Comparison of the in vivo PK results for formulations CF4 and CF5 shows that the birepiperazole particle size D (90) has a significant impact on the drug release rate. During the study, significant reservoir residue was observed at the injection site of formulation CF1 on day 287.

[0245] Figure 2 The graph shows the blood concentration-time curve after subcutaneous injection of long-acting birepiperazole with formulation CF5-7 into rats; contrast Figure 2 The pharmacokinetic curves of formulations CF5 or CF6 and CF7 show that when the active ingredient is in the form of birepiperazole hydrochloride, the drug release in vivo is relatively faster after administration. The pharmacokinetic curves of formulations CF5 and CF6 show that after increasing the drug loading, the exposure of birepiperazole in plasma increases slightly, which is positively correlated with the dose, indicating that the adjustment of the drug loading has no significant effect on drug release.

[0246] Figure 3 The graph shows the blood concentration-time curves after subcutaneous injection of long-acting birepiperazole with formulations CF8 and CF9 into rats; from Figure 3 The experimental results showed that the blood drug concentrations of CF8 and CF9 rats were low after subcutaneous administration, remaining below 10 ng / ml for approximately 24 hours. Drug release was low, and even 800 hours after administration, drug residues remained in the animals, indicating incomplete drug release. (Comparison with CF8 and...) Figure 1 The CF1 curve suggests that the large molecular weight of the biodegradable polymer may have caused drug retention. During the experiment, it was also found that both the CF8 and CF9 formulations exhibited significant bulging during the animal experiments, which did not subside by the end of the experiment. This indicates that although the CF8 and CF9 formulations can achieve sustained release, the severe drug retention and low blood drug concentrations prevent them from meeting the expected targets in terms of safety and efficacy.

[0247] Figure 4The graph shows a comparison of blood concentration-time curves after subcutaneous injection of long-acting birepiperazole formulations of CF5, CF12, and CF13 into rats. A pharmacokinetic (PK) comparison of formulations CF12 and CF13 with CF5 shows that drug compositions combining low molecular weight biodegradable copolymer diblock and triblock copolymers with birepiperazole having a particle size D90 distribution of 2–5 μm exhibit superior in vivo PK results.

[0248] Figure 5 The following are pharmacokinetic curves showing the effects of subcutaneous injection of CF12 long-acting birepiperazole at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg in dogs. Detailed Implementation

[0249] To better understand the technical solution of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0250] Preparation example: Biodegradable polymers The required amount of PEG (providing a triblock copolymer) or methoxy-PEG (providing a diblock polymer) is added to ethyl acetate and stirred. Then, the catalyst amount of stannous octoate or zinc lactate and D,L-lactide (corresponding to the target lactic acid / epoxy ethylene oxide molar ratio) are added. The mixture is heated under nitrogen and refluxed. After the reaction is completed, ethyl acetate and activated carbon are added and heated and stirred. The mixture is then cooled to room temperature and filtered to obtain the diblock copolymer mPEG-PLA or the triblock copolymer PLA-PEG-PLA.

[0251] pass 1 The obtained products were characterized by H-NMR integration method, and by 1 The number-average molecular weight of the block copolymer can be calculated from the peak areas of the characteristic peaks of LA and EO in the H-NMR spectrum. 1 H-NMR integration can not only calculate molecular weight, but also determine the number of repeating units by measuring the integral area ratio of characteristic peaks at the ends of polymer chains (such as the CH3 end-base peak of mPEG and the CH end-base peak of PLA), thus confirming the chemical structure.

[0252] Gel permeation chromatography (GPC) can further characterize the obtained products to determine their molecular weight distribution. GPC is gel permeation chromatography equipped with a differential refractive index detector, using polystyrene standards to further characterize the obtained products and determine their molecular weight distribution. The molecular weight distribution is characterized by number-average molecular weight (Mn), weight-average molecular weight (Mw), and polymer dispersity (PDI).

[0253] It should be understood that, due to 1¹H-NMR calculates the weight ratio of each segment by integrating the peak area, reflecting the actual proportion of chain end groups or characteristic groups. This method is usually very accurate in obtaining Mn (e.g., error range of ±5% to ±10%), especially for block copolymers as described in this invention. GCP measures relative molecular weight, which has a relatively larger error. 1 The Mn calculated by H-NMR integration and the Mn measured by GPC may have certain errors, which are acceptable as long as they are within a reasonable range as deemed so by those skilled in the art. The diblock copolymers and triblock copolymers described in this invention preferably employ... 1 The structure of the polymer was confirmed by H-NMR integration, and GPC was used to further verify whether the target product was successfully synthesized. Generally, when PDI < 1.2, it indicates that the synthesized target copolymer is relatively pure.

[0254] The diblock copolymers (DB) used in the following examples are composed of polylactic acid (PLA) and polyethylene glycol (PEG), with a number average molecular weight of 300 to 21,600 Da, and contain 30 to 95% by weight of PLA, preferably 30 to 80% by weight of PLA. The triblock copolymers (TB) are composed of PLA and PEG, with a number average molecular weight of 400 to 21,600 Da, and contain 40 to 95% by weight of PLA, preferably 50 to 80% by weight of PLA.

[0255] Exemplary methods for preparing diblock copolymers and triblock copolymers are shown below.

[0256] (1) The preparation method of the diblock copolymer mPEG200-PLA100 is as follows: Add 40g of mPEG with a molecular weight of 200 Da and 200ml of ethyl acetate to a 500ml three-necked flask. Add D,L-lactide (30g) and stannous octoate (1.68g) while stirring. Purge with nitrogen and heat to reflux. After the reaction is complete, cool to room temperature, add ethyl acetate and activated carbon, purge with nitrogen, heat to 60~70℃ and continue stirring for 2~3 hours. Cool to room temperature, filter, and concentrate to obtain the target copolymer, which is denoted as diblock copolymer (mPEG:200Da, PLA:100 Da).

[0257] 1 H-NMR (CDCl3) yielded a number-average molecular weight of 300 Da; GCP determination showed that the polymer dispersity (PDI) was 1.19.

[0258] (2) Preparation of triblock copolymer PLA100-PEG200-PLA100 Add PEG (30.00 g) and ethyl acetate (150 ml) with a molecular weight of 200 Da to a 500 ml reaction flask. Add D,L-lactide (45.00 g) and stannous octoate (1.90 g) while stirring. Purge with nitrogen and heat to reflux. After the reaction is complete, cool to room temperature, add ethyl acetate and activated carbon, heat to 60-70°C under nitrogen protection and stir for 2-3 hours. Cool to room temperature, filter, and concentrate to obtain the target copolymer, denoted as TB (PEG: 200 Da, PLA: 200 Da).

[0259] 1 H-NMR (CDCl3) yielded a number-average molecular weight of 416.4 Da; GCP determination showed that the polymer dispersion PDI was 1.10.

[0260] (3) Preparation of diblock copolymer mPEG200-PLA600 Add 15.01 g of mPEG (mPEG: 200 Da), 45.02 g of D,L-lactide, and 75 ml of ethyl acetate to a reaction flask, stir well, add 0.63 g of stannous octoate, purge with nitrogen, heat to reflux overnight, cool to room temperature, add ethyl acetate and activated carbon, heat to 60-70°C and stir for 2-3 hours, cool to room temperature, filter, and concentrate to obtain the target copolymer, denoted as DB (mPEG: 200 Da, PLA: 600 Da).

[0261] 1 H-NMR (CDCl3) yielded a number-average molecular weight of 800 Da; GCP determination showed that the polymer dispersity (PDI) was 1.47.

[0262] (4) Preparation of triblock copolymer PLA300-PEG200-PLA300 Add PEG (15.00 g), D,L-lactide (45.01 g), and ethyl acetate (75 ml) with a molecular weight of 200 Da to the reaction flask, stir well, add stannous octoate (0.63 g), purge with nitrogen, heat to reflux until the reaction is complete, cool to room temperature, add ethyl acetate and activated carbon, heat to 60~70℃ and stir for 2~3 hours, cool to room temperature, filter, and concentrate to obtain the target copolymer, denoted as TB (PEG: 200 Da, PLA: 600 Da).

[0263] 1 H-NMR (CDCl3) yielded a number-average molecular weight of 800 Da; GCP analysis showed a polymer dispersity index (PDI) of 1.21.

[0264] Referring to the methods in (1) and (3) above, the required amount of mPEG is reacted with the required amount of D,L-lactide to prepare diblock polymers mPEG2000-PLA19600 and mPEG350-PLA1150 of the corresponding molecular weights. Referring to the methods in (2) and (4) above, react the required amount of PEG with the required amount of D,L-lactide to prepare triblock polymers of corresponding molecular weights, PLA9800-PEG2000-PLA9800 and PLA1630-PEG1000-PLA1630, respectively denoted as TB (PEG: 2000Da, PLA: 19600Da) and TB (PEG: 1000Da, PLA: 3260Da).

[0265] Where TB (PEG: 2000Da, PLA: 19600Da): 1 H-NMR (CDCl3): 21995, polymer dispersion PDI is 1.21; TB (PEG: 1000Da, PLA: 3260Da): 1 H-NMR (CDCl3): 4369, polymer dispersion PDI is 1.13.

[0266] Example 1: Preparation of an ibuprofen pharmaceutical composition In injectable long-acting birepiperazole formulations, the active ingredient can be prepared by micronization or grinding, followed by sieving to obtain birepiperazole or its pharmaceutically acceptable salt that meets particle size requirements.

[0267] Preparation method: Weigh the prescribed amounts of DB and TB, add them to DMSO, stir to completely dissolve the polymer, then add the prescribed amounts of raw materials to the above materials, stir to dissolve the raw materials, and the product is obtained.

[0268] Exemplary formulations of long-acting birepiperazole injections are shown in Tables 1.1 to 1.5: Table 1.1: Prescriptions CF1~CF3

[0269] Table 1.2: Prescriptions CF4~CF6

[0270] Table 1.3: Prescriptions CF7~CF9

[0271] The active ingredient in prescription CF7 is birepiperazole hydrochloride. (89) This refers to the dosage of birepiperazole hydrochloride.

[0272] Table 1.4: Prescriptions CF10~CF12

[0273] Table 1.5: Prescriptions CF13~CF15

[0275] Example 2: Pharmacokinetic Study of Biriperazole Long-Acting Injection in Rats The experimental animals were male SD rats, weighing approximately 200g. They were administered the corresponding test product via subcutaneous injection into the neck and back at the doses shown in Table 2.1 according to their groups. Plasma was collected at different time points after administration, and the concentration of biriperazole in the plasma was analyzed.

[0276] The blood collection time points for prescriptions CF1-CF5 are: 2h, 7h, 1d, 2d, 3d, 4d, 5d, 6d, 8d, 10d, 14d, 17d, 20d, 24d and 28d; Blood collection time points for prescription CF6 and CF7 are: 2h, 7h and 1d, 2d, 3d, 4d, 5d, 6d, 8d, 10d, 14d, 17d, 20d, 24d, 28d, 32d and 36d; Blood collection time points for prescription CF8 and CF9 are: 2h, 7h and 1d, 2d, 3d, 4d, 5d, 6d, 8d, 10d, 14d, 17d, 20d, 24d, 28d and 32d; Blood collection time points for prescriptions CF12 and CF13 are: 2h, 7h, and 1d, 2d, 3d, 4d, 5d, 6d, 8d, 10d, 14d, 17d, 20d, 24d, 28d, 31d, 35d and 42d.

[0277] Based on the drug's plasma concentration data, the pharmacokinetic parameters AUC, Cmax, and Tmax of the test sample were calculated using Phoenix Winnonlin 6.1 software. The corresponding plasma drug concentration-time curves are shown below. Figures 1-4 As shown.

[0278] Table 2.1

[0279] like Figures 1-4 The results of the study show that the formulation disclosed in this invention has a release curve of not less than 1 month at different doses, and can quickly establish a stable plasma concentration of birepiperazole. It can release rapidly at the beginning of administration, and after the first release peak, the drug can be released stably for not less than 28 hours.

[0280] from Figures 1-4The experimental results show that the long-acting biriperazole injection provided by this invention maintains a blood concentration of biriperazole for 28 days or more after a single dose, allowing for dosing every 4 weeks or longer. Currently, biriperazole used clinically requires daily dosing to ensure sustained efficacy. Therefore, the long-acting biriperazole injection provided by this invention prolongs the release time of biriperazole after entering the body and maintains a high concentration of biriperazole detectable over a longer period, such as 28 days ± 5 days. The experimental results also show that the long-acting biriperazole injection provided by this invention maintains a relatively stable blood concentration for a long time after a single dose, with a low peak-to-trough ratio and minimal fluctuations in blood concentration, indicating fewer side effects. Furthermore, the drug composition provided by this invention exhibits a good drug release rate and low reservoir residue within the set timeframe, such as 28 ± 5 days.

[0281] Example 3: Pharmacokinetic Study of Long-Acting Ibuprofen Injection in Dogs Male beagle dogs, weighing approximately 8-12 kg, were used as experimental animals. They were administered the corresponding test drug via subcutaneous injection into the neck and back at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg, respectively. Plasma samples were collected at 2 h, 8 h, and 1 d, 2 d, 3 d, 5 d, 7 d, 8 d, 10 d, 12 d, 14 d, 16 d, 18 d, 20 d, 23 d, 26 d, 29 d, 32 d, 35 d, 38 d, 41 d, 45 d, and 49 d after administration, and the plasma concentration of biriperazole was analyzed. Based on the drug's plasma concentration data, the pharmacokinetic parameters AUC, Cmax, and Tmax of the test drug were calculated using Phoenix Winnonlin 6.1 software.

[0282] Figure 5 The pharmacokinetic curves of CF12 long-acting birepiperazole injection administered subcutaneously to the neck and back of dogs at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg are shown. As can be seen from days 0 to 5, the drug release is low, while from days 5 to 35, the drug is released steadily and continuously in the body, and the blood drug concentration is dose-dependent.

[0283] Pharmacokinetic studies of long-acting birepiperazole injections (formulas C13-CF15) in dogs showed that they had similar effects to formulation CF12.

[0284] Example 4: Stability Study Samples of birepiperazole long-acting injection with formulations CF1-CF14 prepared in Example 1 were placed at a temperature of 2-8°C. Samples were taken on days 0, 1, 5, 16, 21, 44, 51, 106, and 113 to detect changes in the particle size of the active pharmaceutical ingredient (API) in the drug composition, and compared with the API particle size (D90) on day 0. The experimental results show that the drug composition provided by this invention has good stability when placed at 2-8°C, and the particle size of the API in the drug composition remained essentially unchanged from day 0 to day 113.

Claims

1. A pharmaceutical composition for injection, said pharmaceutical composition comprising: (a) Buripiperazole or a pharmaceutically acceptable salt thereof; (b) A biodegradable copolymer comprising at least one of a diblock copolymer or a triblock copolymer; in, The diblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 200-1500 Da; The triblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 200-4500 Da; (c) A water-soluble organic solvent, wherein the water-soluble organic solvent is at least one of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol or isopropanol; Preferably, the pharmaceutical composition comprises, by weight, 5-35% bripiprazole or a pharmaceutically acceptable salt thereof, 10-45% a biodegradable copolymer, and 35-80% a water-soluble organic solvent. More preferably, the pharmaceutical composition comprises 10-35% by weight of birepiperazole or a pharmaceutically acceptable salt thereof; More preferably, the pharmaceutical composition comprises 10-40% by weight of a biodegradable copolymer; More preferably, the pharmaceutical composition contains 35-70% by weight of a water-soluble organic solvent.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises 10-30% by weight of birepiperazole or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition contains 40-70% by weight of a water-soluble organic solvent; Preferably, the water-soluble organic solvent is one or a mixture of DMSO, N-methylpyrrolidone, N,N-dimethylformamide, or ethanol.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises 15 to 40% by weight of a biodegradable copolymer.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the biodegradable copolymer comprises a diblock copolymer and a triblock copolymer; the content of the diblock copolymer in the pharmaceutical composition is 10 to 45% by weight, preferably 10 to 25% by weight; the content of the triblock copolymer in the pharmaceutical composition is 0 to 45%, preferably 5 to 15% by weight, and the total amount of the diblock copolymer and the triblock copolymer in the pharmaceutical composition is 10 to 45% by weight, preferably 15 to 40% by weight.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that, The diblock copolymer contains 30-95% by weight of polylactic acid, preferably 30-80% by weight of polylactic acid; Further preferably, the terminal hydroxyl groups at one end of the polyethylene glycol chain in the diblock copolymer are C 1~3 The alkyl end is capped, and the terminal hydroxyl group at the other end forms an ester bond with the polylactic acid chain; More preferably, the diblock copolymer has the structure shown in Formula I: , where n represents the number of repeating units of ethylene oxide (-CH2CH2O-) in polyethylene glycol (PEG), and m is the number of repeating units of lactic acid in polylactic acid (PLA).

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that, The triblock copolymer contains 40-95% polylactic acid, preferably 50-80% polylactic acid; Further preferably, the triblock copolymer is obtained by forming ester bonds between the terminal hydroxyl groups at both ends of the polyethylene glycol chain and the polylactic acid chain; More preferably, the triblock copolymer has the structure shown in Formula II: ， Where y is the number of repeating units of ethylene oxide (-CH2CH2O-) in polyethylene glycol (PEG), and x is the number of repeating units of lactic acid in polylactic acid (PLA).

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The number-average molecular weight of the diblock copolymer is 300-1500 Da, preferably 300-800 Da; and / or, The number-average molecular weight of the triblock copolymer is 300~1500 Da, preferably 300~800 Da.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that, In the pharmaceutical composition, the particle size distribution of buripiperazole or its pharmaceutically acceptable salt has the following characteristics: D90 is 1 μm to 30 μm, preferably 1 μm to 25 μm, or 2 μm to 25 μm, or 2 μm to 15 μm, or 5 μm to 20 μm, or 2 to 10 μm.

10. A pharmaceutical preparation, characterized in that, The unit dose includes: (a) 50-900 mg of biriperazole, or an equimolar amount of its pharmaceutically acceptable salt; (b) 50 to 500 mg of a biodegradable copolymer, wherein the biodegradable copolymer comprises diblock copolymers and triblock copolymers; The diblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 100-1500 Da, and the diblock polymer contains 30-95% by weight of polylactic acid, preferably 30-80% by weight of polylactic acid. The triblock copolymer comprises polylactic acid and polyethylene glycol, with a number average molecular weight of 100-4500 Da, and the triblock polymer contains 30-95% by weight of polylactic acid, preferably 50-80% by weight of polylactic acid; (c) 100~300 mg of a water-soluble organic solvent, wherein the water-soluble organic solvent is selected from DMSO, NMP, DMAC, ethanol or a combination thereof; Further preferably, the particle size of the buripiperazole or its salt is 2~25μm, or 5μm~20μm, preferably 2~10μm.

11. A method for preparing a pharmaceutical composition according to any one of claims 1 to 9 or a pharmaceutical formulation according to claim 10, the method comprising: Water-soluble organic solvents or biodegradable copolymers are added to birepiperazole or its pharmaceutically acceptable salts.

12. Use of the pharmaceutical composition of any one of claims 1 to 9 or the pharmaceutical preparation of claim 10 in the preparation of a medicament for the treatment and / or prevention of central nervous system diseases; wherein the central nervous system diseases are selected from schizophrenia, bipolar disorder or depression.

13. A biodegradable copolymer comprising diblock copolymers and triblock copolymers, wherein the diblock copolymer comprises polylactic acid and polyethylene glycol, having a number-average molecular weight of 200-1500 Da; and the triblock copolymer comprises polylactic acid and polyethylene glycol, having a number-average molecular weight of 200-4500 Da; Preferably, the number-average molecular weight of the diblock copolymer is 300-1500 Da, and the number-average molecular weight of the triblock copolymer is 300-1200 Da. Further preferably, the number-average molecular weight of the diblock copolymer is 300-800 Da; the number-average molecular weight of the triblock copolymer is 300-800 Da.

14. The biodegradable copolymer of claim 13, wherein the diblock copolymer comprises 30-95% by weight of polylactic acid, preferably 30-80% by weight of polylactic acid; Further preferably, the terminal hydroxyl groups at one end of the polyethylene glycol chain in the diblock copolymer are C 1~3 The alkyl end is capped, and the terminal hydroxyl group at the other end forms an ester bond with the polylactic acid chain.

15. The biodegradable copolymer of claim 13, wherein the triblock copolymer comprises 40-95% by weight of polylactic acid, preferably 50-80% by weight of polylactic acid; Further preferably, the triblock copolymer is obtained by forming ester bonds between the terminal hydroxyl groups at both ends of the polyethylene glycol chain and the polylactic acid chain.

16. The biodegradable copolymer according to claim 13, wherein the number-average molecular weight of polyethylene glycol in the diblock copolymer is about 100-500 Da and the number-average molecular weight of polylactic acid is about 100-1200 Da; and the number-average molecular weight of polyethylene glycol in the triblock copolymer is about 100-1000 Da and the number-average molecular weight of polylactic acid is about 100-3500 Da.

17. Use of the biodegradable copolymer according to any one of claims 13 to 16 in the preparation of medicaments for treating and / or preventing diseases of the central nervous system; Preferably, the biodegradable copolymer is added to a water-soluble organic solvent and a pharmaceutical active ingredient to prepare a biodegradable drug delivery composition.

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