A long-acting epiriprazole in-situ phase-change gel injection and a preparation method thereof

Abstract

The present invention provides a long-acting in-situ phase-change gel injection of epriprazole and a preparation method thereof. The in-situ phase-change gel injection is a sustained-release preparation for injection, which is prepared by dissolving the water-insoluble drug epriprazole in NMP with phospholipid as a matrix, has excellent physical and chemical stability, and the drug release time can be maintained for up to 2 months. In addition, the preparation process is simple, the equipment requirements are low, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to a stable and sustainable-releasing epiriprazole in-situ phase-change gel injection. Background Art

[0002] Brepiprazole is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound jointly developed by Lundbeck of Denmark and Otsuka Pharmaceutical of Japan. It is considered to be another blockbuster product after aripiprazole, with better efficacy and tolerability. Its tablets were approved by the FDA for marketing in August 2015, mainly for schizophrenia and adjuvant treatment of major depression. However, for patients with mental illness, the medication compliance of oral tablets is very poor, which further leads to the high recurrence rate of such diseases.

[0003] Long-acting injections can significantly improve the problem of poor medication compliance among psychiatric patients. By administering drugs by injection, doctors and caregivers can easily find out whether patients have missed injections; at the same time, the half-life of long-acting injections is often longer, which can reduce the burden of daily medication for patients and make continuous treatment simpler. The currently available long-acting injections of aripiprazole (Abilify Maintena, Aristada, and Aristada Initio) can be injected once every January or February, and are increasingly favored by doctors and patients in clinical practice. However, there is currently no long-acting injection of irinotecan on the market. The development of a long-acting injection of irinotecan that can be released continuously has very broad application prospects and huge commercial value.

[0004] At present, there are not many long-acting injection patents for ipirazole at home and abroad, mainly from the original manufacturer Otsuka Pharmaceutical. The patents for long-acting injections involving different sustained-release mechanisms of ipirazole are CN104254530, CN107536802, and CN108186556. The technologies of ipirazole long-acting injections disclosed in these patents can be divided into two types: 1) aqueous suspensions with specific particle sizes and crystal forms; 2) gel compositions with specific particle sizes.

[0005] The aqueous suspension of irinotecan disclosed in CN104254530 and CN107536802 has the same design principle as the marketed AbilifyMaintena, which uses irinotecan dihydrate as raw material and controls the product particle size within a certain range through wet ball milling to achieve the purpose of long-term effect. Animal test data show that the long-acting dosage form can release irinotecan continuously for about 1 month after intramuscular injection.

[0006] CN108186556 discloses a patent for a gel composition containing aripiprazole or epiriprazole, wherein the gel composition suspends epiriprazole with a specific particle size in a carrier solution, and then crushes it to the desired product particle size to form a gel suspension system, which can be injected intramuscularly or subcutaneously. The administration cycle of the preparation can be once a month, once every two or three months. However, the patent embodiment only discloses the animal test data of aripiprazole, and does not disclose the relevant data that epiriprazole can achieve long-term release.

[0007] However, research has found that the above patented technology of Otsuka Pharmaceutical Co., Ltd. has the following problems:

[0008] 1) Poor stability: Whether it is a water suspension or a gel composition, aripiprazole cannot be completely dissolved, and the particles are easy to aggregate in the suspension system. Taking the marketed Abilify Maintena as an example, since the aripiprazole suspension is unstable, it needs to be reconstituted after freeze-drying to prevent the particles from aggregating and precipitating.

[0009] 2) High requirements for APIs: The long-acting mechanism of suspension injections is mainly determined by the product particle size, so the particle size of the API needs to be strictly controlled. For example, in addition to the particle size requirements, products such as Abilify Maintena also need to control the crystal form of the API. In addition, suspension injections usually require sterile raw materials, which will significantly increase the cost of raw materials.

[0010] 3) Complex process and high equipment requirements: The preparation methods of the above patents all require the preparation of the ipiprazole carrier solution first, and then the product particle size is controlled within the target range by sterile ball wet milling or high-pressure homogenization. The production process is relatively complex and requires special equipment such as ball mills, which increases production costs.

[0011] 4) The release time has no significant advantage over existing preparations: The release time of the irinotecan suspension is about 30 days. Although patent CN108186556 states that the administration cycle of its gel composition can reach once every 2 months or once every 3 months, the patent does not provide animal experimental data of the irinotecan gel composition, and its actual release time is unclear.

[0012] CN107213136, CN106963746 and CN106822039 disclose a long-acting injection of ipriprazole. The patent adopts a long-acting technology using PLGA microspheres as a carrier. The drug loading capacity of this technology is generally low, and its preparation process requires the use of toxic and harmful organic solvents such as dichloromethane, which has a high risk of solvent residues. In addition, although the patent discloses a small number of ipriprazole embodiments, there is a lack of corresponding in vivo test data to support the achievement of a long-acting effect.

[0013] In-situ phase change gel technology is another effective means of preparing long-acting injections. After injection, it can form a fixed, non-flowing drug reservoir, thereby achieving the purpose of sustained drug release. Among the widely studied in-situ phase change gels, phospholipid gels have great advantages, mainly because phospholipid gels have multiple advantages such as abundant resources, non-toxicity, good biocompatibility, and injectable administration.

[0014] Patent CN102526753B discloses an in-situ phase-change gel sustained-release system with phospholipid as the matrix and its preparation method. The patent method is essentially an improvement on the CN101027065A method. Ethanol is used to replace the propylene glycol in CN101027065A to dissolve the phospholipids, and injection oil is added to reduce the amount of ethanol and reduce irritation. The medicine disclosed in the patent does not include epiridol, and the gel obtained in most embodiments is a milky yellow opaque liquid. It is speculated that the medicine may not be completely dissolved. The inventor tried to test epiridol according to the prescription disclosed in Example 12 of patent CN102526753B, and only a milky yellow suspension was obtained.

[0015] Patent CN107049932A discloses a phase-change gel composed of phospholipids / Span / ethanol. Some Span (such as Span 80) is added to the formula of the gel, thereby shortening the phase change time of the phospholipid gel after contacting water, allowing it to "instantly solidify", thereby reducing the sudden release of drugs. In the embodiment of the epiridol gel, in vivo tests on rats showed that the release time can last for 25 days, but for poorly soluble drugs such as epiridol, the gel using this formula also has the problem that the drug cannot be completely dissolved. For example, the gel in Example 3 is a milky yellow suspension with high viscosity and poor fluidity.

[0016] CN103705442B, CN103705439B, CN108567736A, CN103816111B and CN103179951B disclose methods for preparing gels using ethanol as an organic solvent. The inventors have found that ethanol is not suitable as a solvent for the gel system for poorly soluble drugs such as epiriprazole. In addition, most of the methods of the above patents use a relatively high concentration of phospholipids to achieve sustained release of drugs. Although high concentrations of phospholipids may bring good sustained-release effects, excessive phospholipid concentrations may cause excessive viscosity and poor fluidity of the product, leading to difficulty in injection; at the same time, excessive phospholipid concentrations may also bring stability risks to the product and increase the probability of crystallization of the product.

[0017] CN102008728B and CN104661648B disclose an in-situ gel system with phospholipids and NMP, which is composed of phospholipids, oxygen-containing organic solvents (lactams, NMP and dimethyl sulfoxide), diacyl lipids and / or tocopherol. However, according to Examples 4 and 12 disclosed in patent CN102008728B, the preparation has the risk of poor stability. Example 4 shows that the preparation needs to be mixed immediately before use, because the drug is not completely dissolved in the PC / GDO / EtOH system, and a suspension containing a poorly soluble active ingredient is obtained. As can be seen from Example 12, the reservoir precursor preparation will crystallize during storage and the lower the temperature, the easier it is to precipitate. The stability time at 25°C is only 2 weeks, indicating that there is a risk of stability of the preparation. The gel liquid disclosed in CN104661648B is a ready-to-use type with poor stability, and the solidified gel produced when it comes into contact with water is liquid crystal. In addition, the above patent disclosures do not include an embodiment of irinotecan. The inventors tried to prepare phospholipid gel using irinotecan as the active pharmaceutical ingredient according to the prescriptions of Example 9 of CN102008728B and Example 11 (A24) of patent CN104661648B, but only a suspension was obtained, and obvious stratification was observed after standing.

[0018] 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 epiprazole. In particular, the study unexpectedly found that the gel prepared with low-concentration phospholipids as the matrix has the advantages of low viscosity and good fluidity, and is easy to inject; more excitingly, the gel injection prepared with low-concentration phospholipids also shows obvious long-acting function. Summary of the invention

[0019] The purpose of the present invention is to provide an improved sustained-release epiriprazole in-situ phase-change gel injection, which solves the problems of poor injectability, poor stability and limited release time in the existing long-acting in-situ gel technology and is particularly suitable for the long-acting in-situ gel injection of the poorly soluble drug epiriprazole.

[0020] To achieve the purpose of the present invention, the following embodiments are provided.

[0021] In one embodiment, a long-acting epiriprazole in situ phase-change gel injection of the present invention comprises epiriprazole as an active pharmaceutical ingredient, gel matrix phospholipids, biocompatible solvent N-methyl-2-pyrrolidone and injection oil.

[0022] In a preferred embodiment, the long-acting epiriprazole in situ phase change gel injection of the present invention is characterized in that: the weight percentages are: epiriprazole 2%~10%, phospholipids 5%~40%, N-methyl-2-pyrrolidone 30%~80% and injection oil 10%~40%; preferably, epiriprazole 4%~8%, phospholipids 10%~25%, N-methyl-2-pyrrolidone 40%~55% and injection oil 18%~40%.

[0023] In the above-mentioned in-situ phase change gel of the present invention, the phospholipids are selected from one or more of natural phospholipids, semi-synthetic phospholipids and synthetic phospholipids; the injection oil is selected from one or more of soybean oil, corn oil, sesame oil, cottonseed oil and medium-chain fatty acid glycerides.

[0024] In a preferred embodiment, in the long-acting injectable epiriprazole in situ phase change gel of the present invention, the phospholipid is a natural phospholipid; more preferably, the natural phospholipid is selected from soybean lecithin, egg yolk lecithin and a mixture thereof, and the injection oil is a medium-chain triglyceride.

[0025] In another embodiment, the present invention also provides a method for preparing the long-acting injectable epiriprazole in-situ phase change gel of the present invention, comprising the following steps:

[0026] 1) dissolving epiliprazole in N-methyl-2-pyrrolidone to prepare epiliprazole solution;

[0027] 2) Add lecithin and injection oil in sequence and stir until completely dissolved;

[0028] 3) The obtained solution is sterilized by filtering through a 0.22 μm filter membrane.

[0029] Preferably, in the above method of the present invention, the phospholipid is soybean lecithin, egg yolk lecithin or a mixture thereof, and the injection oil is medium-chain triglyceride.

[0030] The long-acting epiriprazole in-situ phase-change gel injection provided by the present invention is significantly different from the phospholipid gel disclosed in the prior art. The phospholipid gel disclosed in CN102008728B and CN104661648B uses a specific diacyl lipid (dioleylglycerol, GDO). The inventors have found that the poorly soluble drug epiriprazole is not suitable for this oil system and cannot be completely dissolved. However, a clear and transparent solution can be obtained by adjusting the medium-chain triglyceride of the present invention. No stratification is observed after long-term storage or even centrifugation at 4000rpm, which overcomes the disadvantage that the particles of the suspension injection are easy to aggregate and has better physical stability.

[0031] It is particularly surprising that the epiliprazole phase change gel prepared according to the technical solution of the present invention also has unexpected chemical stability. After being placed under the conditions of 40°C / 75%RH and 25°C / 60%RH for 3 months, the epiliprazole content did not change significantly.

[0032] The in-situ phase-change gel of epirinotecan of the present invention has the advantage of low viscosity and, compared with the high phospholipid concentration gel of the prior art, has better fluidity and injectability, and is particularly suitable for development into an injection to meet the clinical treatment of patients with mental illnesses who have poor medication compliance.

[0033] The in-situ phase-change gel injection of the poorly soluble drug ipriprazole provided by the present invention has the significant advantage of being easy to manufacture. Since the poorly soluble drug ipriprazole can be completely dissolved in the system, there is no requirement for particle size control of the ipriprazole raw material, and non-sterile raw materials can be used for direct production; in addition, the preparation process of the ipriprazole in-situ phase-change gel of the present invention only involves simple dissolution, mixing, and packaging processes, and the process is simple, without special processes such as ball milling and freeze drying, and the equipment requirements are low, and it has the advantages of simple operation, easy control, and low production cost.

[0034] The long-acting gel injection of the prior art requires a higher concentration of phospholipids to maintain the sustained release effect of the drug, and the sustained release time of the drug is mostly limited to less than 1 month. The in-situ phase-change gel injection of the present invention has a significant sustained release effect even at a low concentration of phospholipids. In vivo experimental studies have shown that the long-acting phospholipid phase-change gel of the present invention can be continuously released in vivo for about 2 months, and the sustained release effect is significant. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 : The appearance of the epiriprazole in situ phase-changing 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;

[0036] Figure 2 To compare the appearance of epiliprazole / phospholipid gel, A is the appearance of epiliprazole / phospholipid gel prepared according to Example 12 of CN102526753B, B is the appearance of epiliprazole / phospholipid gel prepared according to Example 3 of CN107049932A, C is the appearance of epiliprazole / phospholipid gel prepared according to Example 9 of CN102008728B, and D is the appearance of epiliprazole / phospholipid gel prepared according to Example 11 of CN104661648B;

[0037] Figure 3 This is the appearance of the sample of ipiprazol / soy lecithin gel after centrifugation;

[0038] Figure 4It shows the phase change phenomenon when the epiriprazole / soy lecithin gel is injected into 0.01 M PBS using a 1 ml syringe and a 26G needle;

[0039] Figure 5 This is the concentration-time curve of ipiprazole phase change gel after subcutaneous injection in rats. DETAILED DESCRIPTION

[0040] The following examples are representative only, to further illustrate and understand the spirit of the present invention, but are not intended to limit the scope of the present invention. Any simple modifications and variations made within the spirit of the present invention are within the scope of the present invention.

[0041] Example 1 Preparation of long-acting injectable epiridol phase-change gel based on soybean lecithin

[0042] Prescription screening: MCT (medium chain triglycerides), GDO (dioleylglycerol), Span-80, ethyl oleate, PVP (polyvinyl pyrrolidone), propylene glycol, Tween-80 were used as auxiliary agents, ethanol, aqueous ethanol and NMP (N-methyl-2-pyrrolidone) were used as solvents, and the phase change gel prescription with soybean lecithin (model: S100) as the matrix was screened. The screening prescription is shown in Table 1 below, and the unit of each component is "g".

[0043]

[0044] Preparation method: Weigh the amount of the raw material of epiprazole in the prescription amount of Table 1, add the corresponding amount of solvent such as NMP and ethanol of various concentrations to dissolve epiprazole; then, add S100 soybean lecithin and thickening aids such as MCT, GDO, ethyl oleate, Pans 80, PVP, propylene glycol and Tween-80 to the resulting solution in sequence, and stir magnetically at room temperature until the lecithin is dissolved. Let it stand until the bubbles disappear. Observe the appearance of the obtained gel. The results in Table 1 show that the gels of prescriptions 2-10 are all suspensions, and only the gel of prescription 1 is a light yellow, clear and transparent liquid. It shows that NMP is more suitable as a solvent for epiprazole gel. In addition, considering the physical stability risk of the suspension, it is preferred that the gel system with NMP as the solvent be further investigated.

[0045] Based on the formulation 1 in Table 1, the formulation of the in-situ phase change gel based on soybean lecithin was further optimized by using NMP as the solvent. The corresponding formulation is shown in Table 2, and the unit of each component is "g".

[0046]

[0047] As shown in Table 2, the gels of prescription numbers 1, 2, 3, 7, 8, and 9 are clear solutions, which are suitable for preparing in-situ phase change gel injections, while the gels of prescription numbers 4, 5, 6, and 10 are suspensions, which are not suitable for preparing in-situ phase change gel injections. Taking into account factors such as the amount of phospholipids, product clarity, and dosage, prescription 2 was determined to be the representative prescription of phase change gels based on soybean lecithin, named as Epiprazole in-situ gel long-acting injection A (see Table 3 for the specific prescription composition), and subsequent viscosity, stability, and drug release were investigated.

[0048]

[0049] Example 2 :Epiprazole phase change gel injection based on egg yolk lecithin

[0050] Prescription screening: MCT (medium chain triglycerides), GDO (dioleylglycerol), Span-80, ethyl oleate, PVP (polyvinyl pyrrolidone), propylene glycol, Tween-80 were used as auxiliary agents, ethanol, aqueous ethanol and NMP (N-methyl-2-pyrrolidone) were used as solvents, and the phase change gel prescription with egg yolk lecithin (model: PL-100M) as the matrix was screened. The screening prescription is shown in Table 4, and the unit of each component is "g".

[0051]

[0052] Preparation process: According to the preparation method of Example 1, first weigh the amount of the ipriprazole raw material in Table 4, add the corresponding amount of solvent NMP or ethanol of different concentrations to dissolve it, and obtain the ipriprazole solution. Subsequently, PL-100M egg yolk lecithin and thickening aids such as MCT, GDO, soybean oil, Pansi 80, PVP, propylene glycol and Tween-80 are added to the resulting solution in sequence, and magnetic stirring is performed at room temperature until the phospholipids are dissolved. Stand still until the bubbles are dispersed. Observe the appearance of the resulting gel. The results in Table 4 show that only the gel of prescription 1 is a golden clear and transparent liquid, and the gels of the other prescriptions are all suspensions, indicating that NMP is suitable as a solvent for ipriprazole / egg yolk lecithin gel. For this reason, NMP is used as a solvent, and the in-situ phase change gel prescription based on egg yolk lecithin is further optimized on the basis of prescription 1. The corresponding prescription is shown in Table 5, and the unit of each component is "g".

[0053]

[0054] As shown in Table 5, the gels of prescription numbers 1, 2, 3, 4, 5, 6, and 9 are yellow clear solutions, which can be made into in-situ phase change gel injections, while the gels of prescription numbers 7, 8, and 10 are suspensions, which are not suitable for making in-situ phase change gel injections. Taking into account factors such as phospholipid dosage, product clarity, and injection dose, prescription 2 was determined as the representative prescription of the phase change gel with egg yolk lecithin as the matrix, named as Epiprazole in-situ gel long-acting injection B (see Table 6 for the specific prescription composition), and subsequent viscosity, stability, and drug release were investigated.

[0055]

[0056] Example 3 :Solubility of epiriprazole in phospholipid gel

[0057] The actual appearance photos of the two types of epiprazole in-situ phase change gel injections A and B prepared according to Example 1 and Example 2 are shown in FIG. Figure 1 By comparison, it can be found that the appearance of the long-acting injection of irinotecan phase-change gel of the present invention is different from that of the gel injection disclosed in patents CN102526753B, CN107049932A, CN102008728B and CN104661648B (see Figure 2 ) have significant differences, mainly manifested in the different solubility of poorly soluble active ingredients, see Table 7.

[0058]

[0059] The results in Table 7 show that the phase-change gel injections of the present invention are all clear and transparent solutions, and the poorly soluble active ingredient, irinotecan, can be completely dissolved without precipitation or crystal precipitation after standing, and no stratification is observed even after centrifugation at 4000 rpm for 5 min (see Figure 3 ); However, when the preparation was carried out according to the prescriptions published in patents CN102526753B, CN107049932A, CN102008728B and CN104661648B, the poorly soluble drug was not completely dissolved, but the dispersion of ipirazole in the phospholipid gel was poor in physical stability. Long-term storage may lead to particle aggregation and precipitation.

[0060] Example 4 :Viscosity of epiriprazole in situ phase change gel injection

[0061] Viscosity is an important indicator of injections and will directly determine the injectability of injections. The present invention measured the viscosity of the ipriprazole in-situ phase change gel injections A and B prepared in Example 1 and Example 2 using a NDJ-8S digital rotational viscometer (rotor #0), and briefly evaluated the injectability of the obtained products using a 1ml syringe and a 26G needle (outer diameter 0.45mm). The viscosity and injectability measurement results of the ipriprazole in-situ gel injection of the present invention were compared and analyzed with the data published in invention patents CN107049932A and CN102526753B, and the results are shown in Table 8.

[0062]

[0063] The in-situ phase-change gel injection of the present invention is prepared by using low-concentration phospholipids. Due to the low concentration of phospholipids, the viscosity of the formed gel system is lower. As shown in the viscosity data of Table 8, the viscosity values ​​of the in-situ phase-change gel injection of the present invention A and B are 13.9cp and 10.1cp respectively, with good fluidity, while the viscosity data published by patents CN102526753B and CN107049932A are all more than 200cp, and the difference is very significant. The results of the comparative test of injectability show that the phase-change gel injection of the present invention can be smoothly injected with a 1ml syringe with a 26G needle, while the products in patents CN102526753B and CN107049932A are difficult to inject with this type of syringe. The above information fully shows the injectability advantage of the in-situ phase-change gel injection of the present invention prepared by the technical solution of the present invention, which can be used for clinical small-dose subcutaneous injection.

[0064] Example 5 :Stability of epriprazole in situ phase change gel long-acting injection

[0065] The in-situ phase change long-acting injections of epiriprazole A and B prepared in Example 1 and Example 2 were divided into 2 ml vials in a 1 ml filling volume, nitrogen-filled for about 30 min, stoppered and capped under a nitrogen atmosphere. They were stored under long-term (25°C / 60%RH) and accelerated (40°C / 75%RH) conditions, and samples were taken within a specified time to test the properties of the injections and the epiriprazole content in the samples was determined by HPLC. The test results of the two epiriprazole long-acting injections under accelerated and long-term conditions are shown in Table 9 and Table 10, respectively.

[0066]

[0067]

[0068] As shown in Table 9, after the long-acting injection of irinotecan in situ phase change gel A was placed under accelerated conditions for 3 months, its properties and irinotecan content did not change significantly. Although the long-acting injection of irinotecan in situ phase change gel B showed a certain degree of color change after being placed under accelerated conditions for 1 month, the content of irinotecan in the gel remained unchanged at the accelerated time of 3 months (see Table 9). The above stability test results show that the long-acting injection of irinotecan in situ phase change gel prepared according to the technical solution provided by the present invention has acceptable stability, and the stability of the long-acting injection prepared with soybean lecithin S100 as the matrix may be better than the gel system formed by egg yolk lecithin PL-100M.

[0069] Example 6 :Sustained release effect of ipiprazol in situ phase change gel long-acting injection

[0070] Healthy male SD rats were selected, weighing about 200-300g (weight deviation within the range of ±15%); 12 rats for each prescription, with 2 spare rats. All rats were fed with standard feed at 20-25℃ and 40-70%RH, and had free access to water and food. The test rats were injected with ipirazole phase change gel injection, with a single dose of 50mg / kg. On days 0, 1, 3, 6, 9, 14, 21, 28, 42, and 60 of administration (0, 24, 72, 144, 216, 336, 504, 672, 1008, and 1440 hours), the orbital blood of the rats was centrifuged and the plasma was separated. The blood drug concentration was determined by LC-MS / MS, and the differences in the pharmacokinetic characteristics of different prescription preparations were compared. The in vivo drug-time curves of ipirazole in situ phase change gel injection A and B prepared according to Example 1 and Example 2 are shown in Figure 2. Figure 5 The corresponding pharmacokinetic parameters are shown in Table 11.

[0071]

[0072] The results show that the in situ phase-change gel long-acting injection of irinotecan A and B of the present invention have better sustained-release effect than the phase-change gel disclosed in patent CN107049932A and F127 thermosensitive gel, and the long-acting advantage is very significant. The sustained-release effect of the in situ phase-change gel long-acting injection of irinotecan A and B of Examples 1 and 2 of the present invention is mainly manifested as t 1 / 2 The two in-situ phase-change gel long-acting injections of epiridol A and B of the present invention have a t 1 / 2 The release time and duration of the drug were 672.2 h and 484.6 h respectively, and the MRT were 590.4 h and 533.8 h respectively. The effective blood concentration of irinotecan can be maintained for a long time, and the drug release time can last for 2 months.

Claims

1. A long-acting epiriprazole in-situ phase-change gel injection, which is composed of an active pharmaceutical ingredient epiriprazole, a gel matrix phospholipid, a biocompatible solvent N-methyl-2-pyrrolidone and an injection oil; the weight percentages of the components are: epiriprazole 4% to 8%, phospholipid 10% to 25%, N-methyl-2-pyrrolidone 40% to 55% and injection oil 18% to 40%; The phospholipids are soybean lecithin, egg yolk lecithin and / or a mixture thereof; The injection oil is medium chain triglyceride.

2. A method for preparing the in-situ phase change gel injection of claim 1, comprising the following steps: 1) dissolving epiliprazole in N-methyl-2-pyrrolidone to prepare epiliprazole solution; 2) Add lecithin and injection oil in sequence and stir until completely dissolved; 3) The obtained solution is sterilized by filtering through a 0.22 μm filter membrane.

3. The method according to claim 2, wherein the injection oil is a medium chain triglyceride, or the phospholipid is soybean lecithin or egg yolk lecithin.

Images