CN111603439A - A kind of long-acting epipiprazole in situ phase change gel injection and preparation method thereof - Google Patents

Abstract

The invention provides a long-acting epipiprazole in-situ phase-change gel injection and a preparation method thereof. The in-situ phase-change gel injection is prepared by dissolving the poorly water-soluble drug epipiprazole in NMP with phospholipid as a matrix to prepare an injectable sustained-release preparation. It has excellent physical and chemical stability, and the drug release time Can last up to 2 months. In addition, the preparation process is simple, the equipment requirements are low, and it is suitable for industrial production.

Description

A kind of long-acting epipiprazole in situ phase change gel injection and preparation method thereof

technical field

The invention belongs to the field of pharmaceutical preparations, in particular to a stable and sustainable release epipiprazole in-situ phase change gel injection.

Background technique

Epiprazole (brexpiprazole) is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound jointly developed by Lundbeck of Denmark and Otsuka Pharmaceutical Company of Japan. Another blockbuster variety after that has better efficacy and tolerance. Its tablets were approved by the FDA in August 2015, and are mainly used for schizophrenia and adjuvant treatment of major depression. However, for psychiatric patients, the medication compliance of oral tablets is very poor, which further leads to a high recurrence rate of this type of disease.

Long-acting injections can significantly improve the problem of poor medication adherence in psychiatric patients. Administration by injection makes it easy for doctors and caregivers to find out whether patients have missed injections; at the same time, long-acting injection drugs tend to have a longer half-life, which can reduce the burden of daily medication for patients and make continuous treatment simpler. Aripiprazole long-acting injections (Abilify Maintena, Aristada, and Aristada Initio) that are currently on the market can be injected once in January or February, and are increasingly favored by doctors and patients in clinical practice. However, there is no long-acting injection of epipiprazole currently on the market, and the development of a long-acting injection of epipiprazole with sustained release has a very broad application prospect and great commercial value.

At present, there are not many long-acting injection patents for the layout of epipiprazole at home and abroad, mainly from the original manufacturer Otsuka Pharmaceutical. There are CN104254530, CN107536802, CN108186556 patents for long-acting injections involving different sustained-release mechanisms of epipiprazole. The technologies for long-acting injections of epipiprazole disclosed in these patents can be divided into two types: 1) with specific particle size and crystal form 2) a gel composition with a specific particle size.

The epipiprazole aqueous suspension disclosed by CN104254530 and CN107536802 has the same design principle as the marketed AbilifyMaintena. It uses epipiprazole dihydrate as raw material, and controls the particle size of the product within a certain range through wet ball milling, thereby achieving long-term effects. the goal of. The animal test data shows that the long-acting dosage form is injected intramuscularly, and the epipiprazole can be released continuously for about 1 month.

CN108186556 discloses a patent for a gel composition containing aripiprazole or epipiprazole, the gel composition suspends epipiprazole with a specific particle size in a carrier solution, and then pulverizes to a desired product particle size, Then a gel-like suspension system is formed, which can be injected intramuscularly or subcutaneously. The formulation can be administered once a month, once every two months, or once every three months. However, only the animal test data of aripiprazole is disclosed in the patent examples, and the relevant data that epipiprazole can achieve long-acting release is not disclosed.

However, after research, it is found that the above-mentioned patented technology of Otsuka Pharmaceutical Company has the following problems:

1) Poor stability: Whether it is an aqueous suspension or a gel composition, epipiprazole cannot be completely dissolved, and the particles are easily aggregated in the suspension system. Taking the marketed Abilify Maintena as an example, since the aripiprazole suspension is unstable, it needs to be reconstituted after lyophilization to prevent particle aggregation and precipitation.

2) High requirements for APIs: The long-acting mechanism of suspension injections is mainly determined by the particle size of the product, so it is necessary to strictly control the particle size of the API, such as Abilify Maintena and other products, in addition to the particle size requirements, it is also necessary to control the crystal form of the API . In addition, suspension injections usually require sterile raw materials, and the cost of raw materials will increase significantly.

3) The process is complex and the equipment requirements are high: the preparation methods of the above patents must first prepare the epipiprazole carrier solution, and then control the product particle size within the target range by means of sterile ball wet milling or high-pressure homogenization. The production process is relatively complicated, requiring special equipment such as ball mills, and the production cost increases.

4) There is no significant advantage in release time compared with existing formulations: the release time of epipiprazole suspension is about 30 days, although patent CN108186556 claims that the administration cycle of its gel composition can be up to 2 months or 3 months Once, but the patent does not provide animal experimental data of the epipiprazole gel composition, and its actual release time is not clear.

CN107213136, CN106963746 and CN106822039 disclose a kind of long-acting injection of epipiprazole. The patent adopts the long-acting technology of PLGA microspheres as the carrier. Toxic and harmful organic solvents, the risk of solvent residues is high; in addition, although the patent discloses a small amount of epipiprazole examples, there is a lack of corresponding in vivo test data to support long-term effects.

In situ phase change gel technology is another effective method for preparing long-acting injections, which can form a fixed and immobile drug reservoir after injection, thereby achieving the purpose of sustained drug release. Among the widely studied in situ phase change gels, phospholipid gels have great advantages, mainly due to the multiple advantages of phospholipid gels, such as abundant resources, non-toxicity, good biocompatibility, and injectable administration.

Patent CN102526753B discloses an in-situ phase-change gel sustained-release system with phospholipids as a matrix and a preparation method thereof. The patented method is essentially an improvement to the method of CN101027065A, replacing propylene glycol in CN101027065A with ethanol to dissolve phospholipids, and adding oil for injection to reduce the amount of ethanol and reduce irritation. The medicine disclosed in this patent does not include epipiprazole, and the gel obtained in most of the examples is a milky yellow opaque liquid, and it is speculated that the medicine may not be completely dissolved. The inventors tried to test epipiprazole according to the formulation disclosed in Example 12 of the patent CN102526753B, and only a milky yellow suspension could be obtained.

Patent CN107049932A discloses a phase change gel composed of phospholipid/span/ethanol. Part of Span (such as Span 80) is added to the formulation of the gel, which shortens the phase transition time of the phospholipid gel after it meets water, so that it can be "immediately solidified", thereby reducing the phenomenon of drug burst release. Wherein the epipiprazole gel embodiment, the rat in vivo test shows that the release time can last for 25 days, but for the insoluble medicine such as epipiprazole, the gel of this prescription also has the problem that the medicine cannot be completely dissolved, For example, the gel of Example 3 is a milky yellow suspension, which has the problems of high viscosity and poor fluidity.

CN103705442B, CN103705439B, CN108567736A, CN103816111B and CN103179951B disclose methods for preparing gel by using ethanol as an organic solvent. The inventors have found that, for poorly soluble drugs such as epipiprazole, ethanol is not suitable for the solvent of the gel system. In addition, most of the methods of the above-mentioned patents use higher concentrations of phospholipids to achieve sustained drug release. Although high concentrations of phospholipids may bring good sustained-release effects, too high concentrations of phospholipids may lead to excessive viscosity and poor fluidity of the product, which may lead to difficulty in injection; The probability that the product will crystallize.

CN102008728B and CN104661648B disclose an in-situ gel system with phospholipids and NMP, the system is composed of phospholipids, oxygenated organic solvents (lactam, NMP and dimethyl sulfoxide), diacyl lipids and/or tocopherols constitute. However, according to Example 4 and Example 12 disclosed in the patent CN102008728B, it is known that this formulation has the risk of poor stability. Example 4 shows that the formulation needs to be mixed immediately before use because the drug is not completely dissolved in the PC/GDO/EtOH system, resulting in a suspension containing a poorly soluble active ingredient. It can be seen from Example 12 that the depot precursor formulation will crystallize during storage and the lower the temperature, the easier it is to precipitate, and the stability time at 25°C is only 2 weeks, indicating that the stability of the formulation is at risk. The gel liquid disclosed in CN104661648B belongs to the ready-to-use type, with poor stability, and the solidified gel produced in contact with water is liquid crystal. In addition, the content disclosed in the above-mentioned patent does not include the embodiment scheme of epipiprazole. According to the prescription of Example 9 of CN102008728B and Example 11 (A24) of patent CN104661648B, the inventor tried to prepare phospholipid gel with ipipiprazole as the active pharmaceutical ingredient, but only a suspension can be obtained, and it can be seen after standing Clearly layered.

The inventors have found that using N-methyl-2-pyrrolidone (NMP) as a biocompatible solvent can not only achieve compatibility with phospholipids, but also better solve the key problem of poor solubility of the poorly soluble drug epipiprazole. In particular, the study unexpectedly found that the gel prepared with low-concentration phospholipids has the advantages of low viscosity, good fluidity, and is easy to inject; more excitingly, the gel injection prepared with low-concentration phospholipids also showed Obvious long-lasting function.

SUMMARY OF THE INVENTION

The object of the present invention is to provide an improved sustainable release epipiprazole in situ phase change gel injection, which solves the problems of poor injectability and poor stability of the existing long-acting in situ gel technology. It is particularly suitable for the long-acting in situ gel injection of the poorly soluble drug epipiprazole.

In order to achieve the purpose of the present invention, the following embodiments are provided.

In one embodiment, a long-acting epipiprazole in situ phase-change gel injection of the present invention comprises a pharmaceutical active ingredient epipiprazole, a gel matrix phospholipid, and a biocompatible solvent N-methyl-2 - Pyrrolidone and oil for injection.

In a preferred embodiment, the long-acting epipiprazole in situ phase change gel injection of the present invention is characterized in that: the weight percentages are: epipiprazole 2%-10%, phospholipid 5%-40%, N -30%~80% of methyl-2-pyrrolidone and 10%~40% of oil for injection; preferably, 4%~8% of epipiprazole, 10%~25% of phospholipids, Pyrrolidone 40%~55% and injection oil 18%~40%.

In the above-mentioned in-situ phase change gel of the present invention, the phospholipid is selected from one or more of natural phospholipids, semi-synthetic phospholipids and synthetic phospholipids; the injection oil is selected from soybean oil, corn oil, sesame oil, cottonseed One or more of oil and medium chain fatty acid glycerides.

In a preferred embodiment, in the above-mentioned long-acting injection epipiprazole in situ phase change gel of the present invention, the phospholipid is a natural phospholipid; more preferably, the natural phospholipid is selected from soybean phospholipid, egg yolk lecithin and A mixture thereof, the oil for injection is a medium chain triglyceride.

In another embodiment, the present invention also provides a method for preparing the above-mentioned long-acting injection epipiprazole in situ phase change gel of the present invention, comprising the following steps:

1) Dissolving epipiprazole in N-methyl-2-pyrrolidone to prepare an epipiprazole solution;

2) Add phospholipids and oil for injection in turn, and stir until completely dissolved;

3) The obtained solution is sterilized by filtration through a 0.22 μm filter membrane, and then it is obtained.

Preferably, in the above method of the present invention, the phospholipid is soybean lecithin, egg yolk lecithin or a mixture thereof, and the oil for injection is medium chain triglyceride.

The long-acting epipiprazole in situ phase-change gel injection provided by the present invention is significantly different from the phospholipid gels disclosed in the prior art. The phospholipid gels disclosed by CN102008728B and CN104661648B use specific diacyl lipids (glycerol dioleate, GDO). The inventors have found that the poorly soluble drug epipiprazole is not suitable for this oil system. The azole cannot be completely dissolved, but a clear and transparent solution can be obtained by adjusting the medium-chain triglyceride of the present invention, and no layering can be seen even after being placed for a long time even in 4000 rpm centrifugation treatment, which overcomes the shortcoming of easy aggregation of suspension-type injection particles. Better stability.

It is particularly surprising that the epipiprazole phase change gel prepared according to the technical solution of the present invention also has unexpected chemical stability. Under the conditions of 40°C/75%RH and 25°C/60%RH for 3 months, the content of epipiprazole did not change significantly.

The epipiprazole in-situ phase change gel of the present invention has the advantages of low viscosity, and compared with the prior art high phospholipid concentration gel, it has better fluidity and injectability, and is especially suitable for being developed into an injection. To meet the clinical treatment of psychiatric patients with poor medication compliance.

The in-situ phase-change gel injection of the poorly soluble drug epipiprazole provided by the invention has the obvious advantage of being easy to manufacture. Since the poorly soluble drug epipiprazole can be completely dissolved in this system, there is no particle size control requirement for the epipiprazole bulk drug, and non-sterile raw materials can be used for direct production; in addition, the epipiprazole of the present invention In-situ phase change gel, the preparation process only involves simple processes such as dissolution, mixing, and sub-packaging. The process is simple, without special processes such as ball milling and freeze-drying. The advantages.

The long-acting gel injections of the prior art require a relatively high concentration of phospholipids to maintain the sustained-release effect of the drug, and the sustained-release time of the drug is mostly limited to within one month. However, the epipiprazole in situ phase change gel injection of the present invention has an obvious sustained-release effect even at a low-concentration phospholipid ratio. In vivo test studies show that the long-acting epipiprazole phospholipid phase-change gel of the present invention can be continuously released in vivo for about 2 months, and the sustained-release effect is remarkable.

Description of drawings

Fig. 1 is the appearance of the epipiprazole in situ disguised gel injection of the present invention, wherein A is the appearance of the gel injection A of Example 1, and B is the appearance of the gel injection B of Example 2;

Fig. 2 compares the appearance of epipiprazole/phospholipid gel, wherein A is the appearance of the epipiprazole/phospholipid gel prepared according to the embodiment 12 of CN102526753B, and B is the appearance of the epipiprazole/phospholipid gel prepared according to the embodiment 3 of CN107049932A The appearance of the phospholipid gel, C is the appearance of the epipiprazole/phospholipid gel prepared according to the embodiment 9 of CN102008728B, and D is the appearance of the epipiprazole/phospholipid gel prepared according to the embodiment 11 of the CN104661648B;

Fig. 3 is the sample appearance of epipiprazole/soybean phospholipid gel after centrifugation;

Figure 4 shows the phase transition phenomenon of epipiprazole/soybean phospholipid gel injected into 0.01M PBS with a 1ml syringe and a 26G needle;

Figure 5 is the drug-time curve of the epipiprazole phase change gel after subcutaneous injection in rats.

Detailed ways

The following examples are only representative to further illustrate and understand the spirit of the present invention, but do not limit the scope of the present invention. Any simple variations and modifications made within the spirit of the present invention fall within the scope of the present invention.

Example 1 Preparation of long-acting injection epipiprazole phase change gel based on soybean phospholipid

Prescription screening: MCT (medium chain triglyceride), GDO (glyceryl dioleate), Span-80, ethyl oleate, PVP (polyvinylpyrrolidone), propylene glycol, Tween-80 as auxiliary agents, Using ethanol, hydrous ethanol and NMP (N-methyl-2-pyrrolidone) as solvents, the formulation of phase change gel based on soybean phospholipid (model: S100) was screened. The screening formula is shown in Table 1 below, and the unit of each component is "g".

Preparation method: take by weighing the epipiprazole crude drug of the recipe quantity of Table 1, add the solvent of corresponding recipe quantity such as NMP, the ethanol of each concentration, make epipiprazole dissolve; Subsequently, in the gained solution, add S100 type soybean lecithin successively and tackifiers such as MCT, GDO, ethyl oleate, Pansi 80, PVP, propylene glycol and Tween-80, and magnetically stirred at room temperature until the phospholipids were dissolved. Let stand until the bubbles dissipate. The appearance of the resulting gel was observed. The results from Table 1 show that the gels of recipes 2-10 are all suspensions, and only the gel of recipe 1 is a light yellow clear and transparent liquid. It is shown that NMP is suitable as the solvent of epipiprazole gel, and considering the risk of physical stability of the suspension, therefore, the gel system with NMP as the solvent is preferred for further investigation.

On the basis of prescription 1 in Table 1, NMP was used as solvent to further optimize the formulation of in situ phase change gel with soybean phospholipid as matrix. The corresponding prescription is shown in Table 2, and the unit of each component is "g".

As can be seen from Table 2, the gels with prescription numbers 1, 2, 3, 7, 8, and 9 are clear solutions and are suitable for making in-situ phase-change gel injections, while the gels with prescription numbers 4, 5, 6, and 10 are For suspension, it is not suitable for in situ phase change gel injection. Considering factors such as phospholipid dosage, product clarity and dosage, it is determined that prescription 2 is a representative prescription of phase change gel with soybean phospholipid as the matrix, named as epipiprazole in situ gel long-acting injection A (specifically The composition of the formula is shown in Table 3), and the follow-up viscosity, stability and drug release are investigated.

Example 2 : Epipiprazole Phase Change Gel Injection Based on Egg Yolk Lecithin

Prescription screening: MCT (medium chain triglyceride), GDO (glyceryl dioleate), Span-80, ethyl oleate, PVP (polyvinylpyrrolidone), propylene glycol, Tween-80 as auxiliary agents, Using ethanol, hydrous ethanol and NMP (N-methyl-2-pyrrolidone) as solvents, the formulation of phase change gel with egg yolk lecithin (model: PL-100M) as matrix was screened. The screening formula is shown in Table 4, and the unit of each component is "g".

Preparation technique: according to the preparation method of Example 1, firstly take the epipiprazole crude drug of the recipe quantity in Table 4, add the solvent NMP of the corresponding recipe quantity or the ethanol of different concentrations to make it dissolve, obtain the epipiprazole solution. Subsequently, PL-100M type egg yolk lecithin and thickening aids such as MCT, GDO, soybean oil, Pansi 80, PVP, propylene glycol and Tween-80 were sequentially added to the resulting solution, and magnetically stirred at room temperature until the phospholipids were dissolved . Let stand until the bubbles dissipate. The appearance of the resulting gel was observed. The results in Table 4 show that only the gel of prescription 1 is a golden yellow clear and transparent liquid, and the gels of other prescriptions are suspensions, indicating that NMP is suitable as a solvent for epipiprazole/egg lecithin gel. To this end, using NMP as the solvent, the formulation of the in-situ phase change gel with egg yolk lecithin as the matrix continued to be optimized on the basis of formulation 1. The corresponding formulation is shown in Table 5, and the unit of each component is "g" .

As can be seen from Table 5, the gels with prescription numbers 1, 2, 3, 4, 5, 6, and 9 are yellow and clear solutions, which can all be made into in-situ phase change gel injections, while the gels with prescription numbers 7, 8, and 10 can be made into in-situ phase change gel injections. The gel is a suspension and is not suitable for in situ phase change gel injection. Considering factors such as phospholipid dosage, product clarity and injection dose, formula 2 was determined as the representative formula of phase change gel with egg yolk lecithin as the matrix, named as epipiprazole in situ gel long-acting injection B ( The specific formulation composition is shown in Table 6), and the follow-up viscosity, stability and drug release were investigated.

Example 3 : Solubility of epipiprazole in phospholipid gels

Figure 1 shows the actual photos of the appearance of the two epipiprazole in situ phase change gel injections A and B prepared according to Example 1 and Example 2. By comparison, it can be found that the appearance of the epipiprazole phase-change gel long-acting injection of the present invention and the gel injections disclosed in the patents CN102526753B, CN107049932A, CN102008728B and CN104661648B have significant differences in appearance (see Figure 2), which is mainly manifested in insoluble The solubility of the active ingredients varies, see Table 7.

The results in Table 7 show that the phase change gel injections of the present invention are all clear and transparent solutions, the insoluble active ingredient epipiprazole can be completely dissolved, no precipitation or crystal precipitation after standing, even after centrifugation at 4000rpm for 5min. There is no delamination phenomenon (see Figure 3); and when prepared according to the prescriptions published in the patents CN102526753B, CN107049932A, CN102008728B and CN104661648B, the complete dissolution of the poorly soluble drug is not achieved, but the epipiprazole is in the phospholipid gel. The resulting dispersion has poor physical stability, and prolonged storage may lead to particle agglomeration, resulting in precipitation.

Example 4 : Viscosity of Epipiprazole In Situ Phase Change Gel Injection

Viscosity is an important indicator of the injection, which will directly determine the injectability of the injection. In the present invention, the viscosity of the epipiprazole in-situ phase change gel injections A and B prepared in Example 1 and Example 2 was measured by NDJ-8S digital rotational viscometer (#0 rotor), and at the same time, the viscosity was measured by 1ml Syringes and 26G needles (0.45mm outer diameter) were briefly evaluated for the injectability of the resulting products. The results of the viscosity and injectability determination of the epipiprazole in-situ gel injection of the present invention are compared and analyzed with the data published in the invention patents CN107049932A and CN102526753B, and the results are shown in Table 8.

The epipiprazole in-situ phase change gel injections of the present invention are all prepared by using low-concentration phospholipids. Due to the low phospholipid concentration, the viscosity of the resulting gel system is lower. As can be seen from the viscosity data in Table 8, the viscosity values of the epipiprazole in-situ phase change gel injections A and B of the present invention are 13.9cp and 10.1cp respectively, and the fluidity is good, while the viscosity data published by patents CN102526753B and CN107049932A Both exceed 200cp, and the difference is very significant. The research results of the injectability comparison test show that the phase change gel injection of the present invention can be injected smoothly with a 1ml syringe with a 26G needle, while the products in the patents CN102526753B and CN107049932A are difficult to inject with this type of syringe. The above information fully demonstrates the injectability advantage of the epipiprazole in situ phase change gel injection prepared by the technical solution of the present invention, and can be used for clinical low-dose subcutaneous injection.

Example 5 : Stability of Epipiprazole In Situ Phase Change Gel Long-acting Injection

The epipiprazole in situ phase change long-acting injections A and B prepared in Example 1 and Example 2 (by 1ml filling volume were divided into 2ml vials, filled with nitrogen for about 30min and plugged under nitrogen atmosphere, rolled The caps were stored under long-term (25°C/60%RH) and accelerated (40°C/75%RH) conditions, and samples were taken within the specified time to check the properties of the injection and the content of epipiprazole in the samples was determined by HPLC. The test results of pipiprazole long-acting injection under accelerated and long-term conditions are shown in Table 9 and Table 10, respectively.

As can be seen from Table 9, after epipiprazole in situ phase change gel long-acting injection A was placed under accelerated conditions for 3 months, its properties and epipiprazole content did not change significantly. Epipiprazole In Situ Phase Change Gel Long-Acting Injection B Although there was a certain degree of color change after being placed under accelerated conditions for 1 month, the content of epipiprazole in the gel remained unchanged after 3 months of acceleration (see Table 9). The above stability test results show that the epipiprazole in situ phase change gel long-acting injection prepared according to the technical solution provided by the present invention has acceptable stability, and the long-acting injection prepared with soybean phospholipid S100 as the matrix has acceptable stability. The stability may be better than the gel system formed by egg yolk lecithin PL-100M.

Example 6 : Sustained release effect of epipiprazole in situ phase change gel long-acting injection

Select healthy male SD rats with a body weight of about 200-300 g (weight deviation within ±15%); 12 rats per prescription and 2 spares. All rats were fed with standard chow at 20-25 ℃ and 40-70% RH with free access to water and food. The test rats were injected with epipiprazole phase-change gel injection, and the dose was 50 mg/kg in a single dose. At 0, 1, 3, 6, 9, 14, 21, 28, 42, and 60 days of administration (0, 24, 72, 144, 216, 336, 504, 672, 1008, 1440 hours), the rats were taken Orbital blood was centrifuged to separate plasma, and LC-MS/MS method was used to determine plasma drug concentration, and the differences in pharmacokinetic characteristics of different prescription preparations were compared. The in vivo drug-time curves of epipiprazole in situ phase change gel injections A and B prepared according to Example 1 and Example 2 are shown in Figure 5, and the corresponding pharmacokinetic parameters are shown in Table 11.

The results show that the epipiprazole in situ phase change gel long-acting injections A and B of the present invention have better sustained-release effects than the phase change gel and F127 thermosensitive gel published in the patent CN107049932A, and the long-term advantage is very high. Significantly. The sustained-release effects of the epipiprazole in situ phase-change gel long-acting injections A and B of Examples 1 and 2 of the present invention are mainly manifested in the prolongation of t _1/2 and MRT. The two epipiprazole in situ phase change gel long-acting injections A and B of the present invention have t _1/2 of 672.2h and 484.6h respectively, and MRT of 590.4h and 533.8h respectively, and can maintain epipiprazole for a long time. The effective blood concentration of azole, the drug release time can last for 2 months.

Claims (10)

1. A long-acting in-situ phase change gel injection of brexpiprazole comprises a pharmaceutical active ingredient brexpiprazole, gel matrix phospholipid, a biocompatible solvent N-methyl-2-pyrrolidone and oil for injection.

2. The in situ phase change gel injection of claim 1, wherein: the weight percentage is as follows: 2-10% of brexpiprazole, 5-40% of phospholipid, 30-80% of N-methyl-2-pyrrolidone and 10-40% of oil for injection.

3. The in situ phase change gel injection of claim 2, wherein: the weight percentage is as follows: 4-8% of brexpiprazole, 10-25% of phospholipid, 40-55% of N-methyl-2-pyrrolidone and 18-40% of oil for injection.

4. The in situ phase change gel injection according to any one of claims 1 to 3, wherein: the phospholipid is selected from one or more of natural phospholipid, semi-synthetic phospholipid and synthetic phospholipid.

5. The in situ phase change gel injection according to claim 4, wherein the phospholipid is a natural phospholipid.

6. The in situ phase transition gel injection according to claim 5, wherein the natural phospholipid is selected from soybean phospholipid, egg yolk lecithin and/or mixture thereof.

7. The in situ phase change gel injection according to any one of claims 1 to 3, wherein the oil for injection is one or more selected from soybean oil, corn oil, sesame oil, cottonseed oil and medium-carbon chain fatty glyceride.

8. The in situ phase change gel of claim 7, wherein the injectable oil is a medium chain triglyceride.

9. A method of preparing the in situ phase change gel injection of claims 1-3 comprising the steps of:

1) dissolving the brexpiprazole in N-methyl-2-pyrrolidone to prepare a brexpiprazole solution;

2) sequentially adding phospholipid and oil for injection, and stirring to dissolve completely;

3) filtering the obtained solution with 0.22 μm filter membrane for sterilization to obtain the final product.

10. The method of claim 9, wherein the oil for injection is medium chain triglyceride, or the phospholipid is soybean phospholipid or egg yolk lecithin.

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