Long-acting brexpiprazole in-situ gel injection and preparation method thereof

Abstract

The invention provides a long-acting brexpiprazole in-situ gel injection and a preparation method thereof. The long-acting brexpiprazole in-situ gel injection is an injectable sustained-release preparation prepared by taking a polylactic acid-glycolic acid copolymer (PLGA) and poloxamer as gel matrixes, dissolving brexpiprazole in an amphiphilic solvent and adding an additive. The long-acting brexpiprazole in-situ gel injection prepared by the invention has good mechanical properties, and the drug release time can be maintained for 1 month. The preparation is simple in preparation process, low in equipment requirement and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a long-acting epipiperazole in situ gel injection and its preparation method. Background Technology

[0002] Brexpiprazole is clinically used to treat schizophrenia and major depressive disorder. It is a dopamine and part of the 5-HT. 1A Receptor agonists and 5-HT 2A Receptor antagonist compounds, whose tablets were approved by the FDA in August 2015, require patients to take the medication orally every day for a long period of time, and are poorly tolerated.

[0003] Long-acting injectable formulations, administered via injection, avoid the risk of overdosing or underdosing associated with oral medications, thus preventing abuse and significantly improving medication adherence in patients with mental disorders. Surveys have revealed a limited number of commercially available in-situ gel formulations; therefore, further research is needed to address most current challenges with in-situ gels, such as efficient and relatively low-cost commercial production and controllable in vivo drug release. Developing a sustained-release, long-acting in-situ gel injection of epipiperazole holds broad application prospects and significant commercial value.

[0004] A review of patents and literature reveals that current domestic and international patents related to long-acting injectable formulations of epipiperazole include patent CN108186556B, which describes a suspension formulation with drawbacks such as poor stability and complex manufacturing processes. Patent CN107049932B discloses a phase change gel composed of phospholipids / Span / ethanol, but high ethanol concentrations can cause skin ulceration. Patents CN103705442B and CN103816111B also disclose methods for preparing gels using phospholipids as the gel matrix. However, for poorly soluble drugs like epipiperazole, ethanol as the solvent in these formulations is not suitable, potentially leading to poor solubility. Furthermore, most of the methods in these phospholipid-based patents require high phospholipid concentrations, which can easily lead to crystallization. Patent CN107213136B discloses an epilapiazole long-acting injection. This patent uses polylactic acid-glycolic acid copolymer (PLGA) microspheres as a carrier. However, its preparation process uses toxic and harmful organic solvents such as dichloromethane, which increases the risk of solvent residue.

[0005] After reviewing patents and literature, there are currently no reports of using carboxyl-terminated PLGA and terminal hydroxyl-terminated poloxamer as gel substrates to prepare in situ gels. The long-acting epipiperazole in situ gel injection prepared for the first time in this invention not only has excellent mechanical properties and can effectively dissolve epipiperazole without organic solvent residue, but also has a simple process and excellent sustained-release effect. Summary of the Invention

[0006] The purpose of this invention is to provide a sustained-release, long-acting epipiperazole in-situ gel injection, which solves the problems of poor injectability, poor stability, and short-acting release time of existing gel injections. It can reduce the frequency of administration, improve patient compliance, and reduce toxic side effects. The long-acting epipiperazole in-situ gel injection provided by this invention has a simple preparation process, low cost, is easy to control, and is easy to industrialize.

[0007] The long-acting epipiperazole in-situ gel injection provided by this invention is characterized by comprising the active pharmaceutical ingredient epipiperazole, the gel matrix polylactic-co-glycolic acid copolymer (PLGA) and poloxamer, an amphiphilic solvent, and excipients. The mass ratio of each component in the formulation is: epipiperazole 0.5-60 parts, PLGA 214-428 parts, poloxamer 120-220 parts, amphiphilic solvent 281-1064 parts, and excipients 9-61 parts. The gel matrix PLGA is selected from carboxyl-terminated compounds, with a structure in which the ratio of lactic acid and glycolic acid monomers is 25:75, 50:50, or 75:25, and a molecular weight of 35,000-57,000; the gel matrix poloxamer is selected from one or both of poloxamer 407 and poloxamer 188; the amphiphilic solvent is selected from one or more of N-methyl-2-pyrrolidone, ethanol, dimethylformamide, ethyl benzoate, dimethylacetamide, ethyl acetate, dimethyl sulfoxide, benzyl benzoate, 2-pyrrolidone, benzyl alcohol, and tetrahydrofuran polyethylene glycol ether; the additive is selected from one or more of glycerol, triacetin, mannitol, methyl heptanoate, povidone, glyceryl monostearate, ethyl heptanoate, methyl nonanoate, and stearic acid.

[0008] The preparation method of the long-acting epipiperazole in situ gel injection provided by the present invention includes the following steps: (1) dissolving epipiperazole in an amphiphilic solvent to prepare solution A; (2) adding polylactic acid-glycolic acid copolymer PLGA and poloxamer to solution A in sequence, mixing evenly to obtain solution B; (3) adding an additive to solution B, mixing evenly to obtain solution C; (4) allowing solution C to stand at room temperature to obtain the long-acting epipiperazole in situ gel injection.

[0009] This invention differs from commonly reported in-situ gels based solely on PLGA. We incorporate poloxamer with terminal hydroxyl groups to form a co-matrix, resulting in superior mechanical properties. This invention is the first to dissolve carboxyl-terminated PLGA and terminal hydroxyl-terminated poloxamer in an amphiphilic solvent, while adding additives to reduce system polarity. This reduces competition for hydrogen bonds between the amphiphilic solvent and PLGA and poloxamer, making hydrogen bond formation between PLGA and poloxamer easier, thus yielding an in-situ gel with faster molding speed and higher mechanical strength. The long-acting epipiperazole in-situ gel injection of this invention is a novel in-situ gel, not previously reported. The long-acting epipiperazole in-situ gel injection provided by this invention completely dissolves epipiperazole, yielding a clear and transparent solution that rapidly solidifies upon contact with aqueous media. Figure 1 The long-acting epipiperazole in situ gel injection provided by this invention also has the advantage of low viscosity, excellent flowability and injectability, and is particularly suitable for development into an injectable form to meet the clinical treatment needs of patients with mental illnesses who have poor medication adherence. Figure 2 ).

[0010] The long-acting epipiperazole in-situ gel injection provided by this invention has the significant advantage of ease of manufacture. Epipiperazole, a poorly soluble drug, can be completely dissolved in this system; therefore, there is no need for stringent particle size control requirements for the epipiperazole raw material. The preparation process of the long-acting epipiperazole in-situ gel injection of this invention involves only simple processes such as dissolution, mixing, and dispensing. The process is simple, requires minimal equipment, and has the advantages of simple operation, easy control, and low production cost.

[0011] In vivo studies of the long-acting epipiperazole in situ gel injection of the present invention show that the long-acting epipiperazole in situ gel injection can be continuously released in vivo for about 1 month, with stable blood drug concentration and significant sustained-release effect. Attached Figure Description

[0012] Figure 1 This invention relates to a long-acting epipiperazole in situ gel injection.

[0013] Experimental conditions: The original state of the long-acting epilapiazole in situ gel injection and its state upon contact with an aqueous medium were observed at room temperature.

[0014] The results show: Figure 1 a represents the appearance of the solidified substance after contact with an aqueous medium; it is a milky white solid. Figure 1 b represents the appearance of the liquid when it is not in contact with an aqueous medium; it is a clear and transparent liquid.

[0015] Figure 2 This is a schematic diagram illustrating the injectability of the long-acting epipipezazole in situ gel injection of the present invention.

[0016] Experimental conditions: The long-acting epipiperazole in situ gel injection was thoroughly stained with methylene blue dye and injected into an aqueous medium using a 0.6×25mm syringe.

[0017] The results showed that the long-acting epipiperazole in situ gel injection prepared by the present invention can be injected into an aqueous medium using a 0.6×25mm syringe, exhibiting good injectability. The in situ gel solidifies rapidly after being injected into water, indicating that it can complete the phase transition in a relatively short time.

[0018] Figure 3 The in vitro release curves of long-acting epipiperazole in situ gel injection and free drug are shown.

[0019] Experimental conditions: An equal volume of long-acting epipiperazole in situ gel injection or free epipiperazole was fully dissolved in 30 mL of phosphate-buffered saline (PBS) (pH 7.4, 1% cetyltrimethylammonium bromide, 0.05% ProClin 300 preservative). The solution was then placed in a sealed dialysis bag (molecular weight cutoff: 8000-14000 Da) and placed in a capped round-bottom flask containing 250 mL of PBS solution. The entire system was shaken at 80 rpm in a constant-temperature shaking bath at 37 ± 0.5 °C. At 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h, and 72 h, 2 mL of the release solution was collected and immediately replenished with an equal volume of fresh release medium at the same temperature. The solution was then returned to the constant-temperature shaking bath. The collected release solution was filtered through a 0.45 μm microporous membrane, and the filtrate was analyzed to calculate the cumulative release rate of the free drug and the drug-containing gel.

[0020] The results showed that the free drug was almost completely released by the end of the first day, while the long-acting epipiperazole in situ gel injection had a drug-containing gel release period of up to 30 days, with a cumulative release of over 90% by the end of 30 days. Compared to the free drug, our prepared long-acting epipiperazole in situ gel injection has a better sustained-release effect.

[0021] Figure 4 The strain frequency scanning results of long-acting epipiperazole in situ gel injections prepared with different excipient mass ratios, i.e., PLGA: poloxamer 100:0, 70:30, 65:35, 50:50 and 30:70 respectively.

[0022] Experimental conditions: The parameters for strain frequency scanning were set as follows: frequency 0.1-10 Hz, shear force γ 1%, and test time 15 min. After measurement, the changes in mechanical strength of the water-based long-acting epipiperazole in-situ gel injection were observed with frequency as the abscissa and storage modulus (G′) and loss modulus (G″) as the ordinates.

[0023] The results showed that, compared with the in-situ gel with PLGA as the gel matrix alone, the long-acting epipiperazole in-situ gel injection with poloxamer formed a composite structure had significantly increased storage modulus and loss modulus at frequencies of 0-10 Hz, while maintaining solid properties across the entire frequency range, indicating a significant improvement in mechanical properties.

[0024] Figure 5 The dynamic shaking test results of long-acting epipiperazole in situ gel injections prepared with different excipient mass ratios, namely PLGA: poloxamer 100:0, 70:30, 65:35, 50:50 and 30:70.

[0025] Experimental conditions: The parameters for strain frequency scanning were set as follows: cyclic strains increasing from 0.1% to 100% were applied at a frequency of ω = 1.0 Hz, and the scan lasted for 10 min. The elasticity and resistance to deformation of the hydrogel were observed by plotting shear force on the x-axis and storage modulus (G′) and loss modulus (G″) on the y-axis.

[0026] The results showed that, compared with the in-situ gel with PLGA as the gel matrix alone, the long-acting epipiperazole in-situ gel injection with the composite structure formed with poloxamer had a higher critical strain value under cyclic strain pressure of 0.1%-100% and then gradually decreased, indicating that the deformation resistance was significantly enhanced.

[0027] Figure 6 Molding speed of long-acting epipiperazole in situ gel injections prepared with different excipient mass ratios. The horizontal axis represents the mass ratio of different excipients, i.e., PLGA: poloxamer are 100:0, 70:30, 65:35, 50:50 and 30:70 respectively.

[0028] Test conditions: The curing speed of the long-acting epilapiazole in situ gel injection was observed when it came into contact with an aqueous medium at room temperature.

[0029] The results showed that, compared with the in-situ gel prepared using PLGA as the gel substrate alone, the long-acting epipiperazole in-situ gel injection with the composite structure formed with poloxamer cured significantly faster.

[0030] Figure 7 The drug-time curves of rats were obtained within 30 days after subcutaneous injection of long-acting epilapiazole in situ gel and oral administration of epilapiazole free drug suspension.

[0031] Experimental conditions: Twelve healthy male SD rats were randomly divided into two groups of six each. One group received long-acting epipiperazole in situ gel injection via subcutaneous injection, while the other group received free epipiperazole via oral administration. The pharmacokinetic behavior of the two formulations in rats was investigated.

[0032] Long-acting epilapiazole in situ gel injection: The single subcutaneous injection dose for each rat is 90 mg / kg.

[0033] Epicipeazole free drug suspension: Each rat was administered the suspension by gavage once daily for 30 days. The dosage was 3 mg / kg. The preparation method of the epicipeazole free drug suspension was as follows: Epicipeazole was dissolved in 0.01 mol / L PBS (pH 7.4) to obtain solution 1. Then, 200 mg / mL of a mixture of 1,2-propanediol and glycerol (mass ratio of 1,2-propanediol to glycerol was 1:3) and 10 mg / mL of glycine were added to solution 1 and mixed thoroughly to obtain the epicipeazole free drug suspension.

[0034] After administration, rat orbital blood was collected at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 120, 168, 216, 288, 360, 432, 504, 576, 648 and 720 h, and plasma was separated by centrifugation. The blood drug concentration was determined by LC-MS / MS, and the differences in pharmacokinetic characteristics of different formulations were compared.

[0035] The results showed that subcutaneous injection of long-acting epipiperazole in situ gel in rats had a significantly sustained-release effect compared to oral epipiperazole free drug suspension. Calculations based on the release curves showed that the median release time (MRT) of the long-acting epipiperazole in situ gel injection was approximately 33 times higher than that of the oral suspension. The average ulcer concentration (AUC) of the long-acting epipiperazole in situ gel injection was approximately 24 times that of the oral epipiperazole free drug suspension.

[0036] Figure 8 The study included the open field behavioral characteristics of the normal group, the schizophrenia model group, the schizophrenia model plus subcutaneous injection of long-acting epilapiazole in situ gel injection group (BP-SRDS), and the schizophrenia model plus oral epilapiazole free drug suspension (BP-Sus) over 28 days.

[0037] Experimental conditions: Forty-eight healthy male SD rats were randomly divided into four groups: Normal group, Model group, BP-SRDS group, and BP-Sus group, with 12 rats in each group. A schizophrenia model was established. The normal group received 1 mL of physiological saline intraperitoneally daily, while the other groups received 0.4 mg / kg of dezocampine (MK-801) intraperitoneally daily for 14 days. After successful modeling, the rats' behavioral characteristics were observed and recorded at 2 h, 1 d, 3 d, 7 d, 14 d, 21 d, and 28 days. On the first day of the test, the BP-SRDS group received a subcutaneous injection of 90 mg / kg of long-acting epipiperazole in situ gel, and no further administration was given. The BP-Sus group received 3 mg / kg of BP-Sus daily by gavage, followed by an intraperitoneal injection of MK-801 at a dose of 0.4 mg / kg after a one-hour wait. After a 15-minute wait, the rats to be tested were placed in the center of a blank open field device equipped with a camera. The total distance traveled by the rats, the duration of fast movement (>10 cm / s), slow movement (<2.5 cm / s), and the time spent stationary were recorded during the 5-minute test period. Before each test, the rats were allowed 5 minutes to familiarize themselves with the field, and the field was thoroughly cleaned with 75% ethanol between each test interval.

[0038] The results show that: Figure 8 At each time point, the total distance traveled by rats in the Model group was significantly greater than that in other groups. The distance traveled by rats after treatment was significantly reduced, while the total distance traveled by rats in the BP-SRDS group showed an increasing trend during the 28-day test period. Figure 8 The percentage of time spent in motor activity at each time point (B) indicates that the Model group rats had a higher proportion of rapid movement time during the test period in the five groups, exhibiting symptoms of psychotic disorder and hyperactivity. During the 28-day test period, the BP-SRDS group rats showed an increasing trend in the proportion of rapid movement time, which significantly decreased after treatment. Furthermore, there was almost no significant difference in the treatment results between BP-SRDS and BP-Sus.

[0039] Figure 9 Social behavioral performance of the Normal, Model, BP-SRDS, and BP-Sus groups over 28 days.

[0040] Experimental conditions: Forty-eight healthy male SD rats were randomly divided into four groups: Normal, Model, BP-SRDS, and BP-Sus, with 12 rats in each group. A schizophrenia model was established. The normal group received 1 mL of physiological saline intraperitoneally daily, while the other groups received 0.4 mg / kg of dezocampine (MK-801) intraperitoneally daily for 14 days. After successful modeling, the rats' behavioral characteristics were observed and recorded at 2 h, 1 d, 3 d, 7 d, 14 d, 21 d, and 28 days. On the first day of the test, the BP-SRDS group received a subcutaneous injection of 90 mg / kg of long-acting epipiperazole in situ gel, and no further administration was given. The BP-Sus group received 3 mg / kg of BP-Sus by gavage daily, followed by a 1-hour wait, and then an intraperitoneal injection of MK-801 at a dose of 0.4 mg / kg. After a 15-minute wait, the two test rats were placed diagonally opposite each other in an open field. The total time spent by the rats during the interaction was recorded and further divided into active interaction (sniffing, following, climbing, grooming, and any aggressive behavior) or passive interaction (close contact). To avoid the passive contact time affecting the results analysis, results were only recorded when the rat contact time was longer than 2 seconds. Before each test, the rats were allowed 5 minutes to familiarize themselves with the area, and the area was thoroughly cleaned with 75% ethanol between each test interval.

[0041] The results showed that during the 28-day test period, if Figure 9 At all time points A and 9B, the social time and frequency of rats in the Model group were significantly lower than those in the other groups, exhibiting typical social deficit symptoms of schizophrenic rats. During the 28-day test period, the social time and frequency of rats in the BP-SRDS group showed less fluctuation. After treatment, BP-SRDS and BP-Sus significantly improved the social deficit in rats, with the effect only weakening at the end of the test, i.e., at the 28-day time point. Furthermore, there was almost no significant difference in the treatment results between BP-SRDS and BP-Sus. Detailed Implementation

[0042] To further illustrate the present invention and its advantages, the following specific embodiments are provided. It should be understood that these embodiments are for illustrative purposes only and not as limiting the scope of the invention.

[0043] Example 1:

[0044] Long-acting epipiperazole in situ gel injection contains epipiperazole, PLGA, poloxamer 407, N-methyl-2-pyrrolidone and ethyl heptanoate, with the following mass ratios being 0.5 parts, 214 parts, 120 parts, 281 parts and 9 parts, respectively.

[0045] Preparation method: (1) Dissolve ipiperazole in N-methyl-2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add ethyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0046] Example 2:

[0047] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, poloxamer 188, dimethyl sulfoxide, and glycerol. The mass ratios of the above components are 6 parts, 272 parts, 100 parts, 75 parts, 352 parts, and 52 parts, respectively.

[0048] Preparation method: (1) Dissolve ipiperazole in dimethyl sulfoxide to prepare solution A; (2) Add PLGA, poloxamer 407 and poloxamer 188 to solution A in sequence, mix well to obtain solution B; (3) Add glycerol to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0049] Example 3:

[0050] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, N-methyl-2-pyrrolidone, and ethyl heptaate. The mass ratios of the above components are 20 parts, 326 parts, 174 parts, 514 parts, and 20 parts, respectively.

[0051] Preparation method: (1) Dissolve ipiperazole in N-methyl-2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add ethyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0052] Example 4:

[0053] Long-acting epipiperazole in situ gel injection contains epipiperazole, PLGA, poloxamer 188, ethyl acetate, N-methyl-2-pyrrolidone, and methyl heptanoate. The mass ratios of the above components are 17 parts, 253 parts, 129 parts, 305 parts, 190 parts, and 37 parts, respectively.

[0054] Preparation method: (1) Dissolve epicipazole in ethyl acetate and N-methyl-2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 188 to solution A in sequence, mix well to obtain solution B; (3) Add methyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting epicipazole in situ gel injection.

[0055] Example 5:

[0056] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, N-methyl-2-pyrrolidone, and ethyl heptaate. The mass ratios of the above components are 22 parts, 292 parts, 138 parts, 922 parts, and 56 parts, respectively.

[0057] Preparation method: (1) Dissolve ipiperazole in N-methyl-2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add ethyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0058] Example 6:

[0059] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, dimethyl sulfoxide, and triacetin. The mass ratios of the above components are 28 parts, 389 parts, 156 parts, 637 parts, and 33 parts, respectively.

[0060] Preparation method: (1) Dissolve ipiperazole in dimethyl sulfoxide to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add triacetin to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0061] Example 7:

[0062] Long-acting epipiperazole in situ gel injection contains epipiperazole, PLGA, poloxamer 188, 2-pyrrolidone, methyl heptaate, and glycerin. The mass ratios of the above components are 33 parts, 233 parts, 147 parts, 708 parts, 15 parts, and 8 parts, respectively.

[0063] Preparation method: (1) Dissolve epiperazole in 2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 188 to solution A in sequence, mix well to obtain solution B; (3) Add methyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting epiperazole in situ gel injection.

[0064] Example 8:

[0065] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, N-methyl-2-pyrrolidone, and triacetin. The mass ratios of the above components are 11 parts, 331 parts, 211 parts, 566 parts, and 18 parts, respectively.

[0066] Preparation method: (1) Dissolve ipiperazole in N-methyl-2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add triacetin to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0067] Example 9:

[0068] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 188, ethyl acetate, and ethyl heptaate. The mass ratios of the above components are 44 parts, 311 parts, 193 parts, 850 parts, and 28 parts, respectively.

[0069] Preparation method: (1) Dissolve ipiperazole in ethyl acetate to prepare solution A; (2) Add PLGA and poloxamer 188 to solution A in sequence, mix well to obtain solution B; (3) Add ethyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0070] Example 10:

[0071] Long-acting epipiperazole in situ gel injection contains epipiperazole, PLGA, poloxamer 188, poloxamer 407, N-methyl-2-pyrrolidone, triacetin, glycerol, and ethyl heptaate. The mass ratios of the above components are 49 parts, 409 parts, 90 parts, 75 parts, 212 parts, 211 parts, 9 parts, and 5 parts, respectively.

[0072] Preparation method: (1) Dissolve ipiperazole in N-methyl-2-pyrrolidone and triacetin to prepare solution A; (2) Add PLGA, poloxamer 407 and poloxamer 188 to solution A in sequence, mix well to obtain solution B; (3) Add glycerol and ethyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

[0073] Example 11:

[0074] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, 2-pyrrolidone, and ethyl heptaate. The mass ratios of the above components are 55 parts, 370 parts, 202 parts, 933 parts, and 47 parts, respectively.

[0075] Preparation method: (1) Dissolve epiperazole in 2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add ethyl heptaate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting epiperazole in situ gel injection.

[0076] Example 12:

[0077] Long-acting epipiperazole in situ gel injection, comprising epipiperazole, PLGA, poloxamer 407, N-methyl-2-pyrrolidone, and methyl heptanoate. The mass ratios of the above components are 60 parts, 428 parts, 220 parts, 1064 parts, and 61 parts, respectively.

[0078] Preparation method: (1) Dissolve ipiperazole in N-methyl-2-pyrrolidone to prepare solution A; (2) Add PLGA and poloxamer 407 to solution A in sequence, mix well to obtain solution B; (3) Add methyl heptanoate to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting ipiperazole in situ gel injection.

Claims

1. A long-acting epipiperazole in situ gel injection, characterized in that, It contains the active pharmaceutical ingredient epipiperazole, the gel matrix polylactic-co-glycolic acid copolymer (PLGA) and poloxamer, an amphiphilic solvent, and additives.

2. The long-acting epipiperazole in situ gel injection according to claim 1, characterized in that, The mass ratio of each component in the long-acting ipiloperazole in situ gel injection is as follows:

3. The long-acting epipiperazole in situ gel injection according to claim 1, characterized in that, The gel matrix polylactic acid-glycolic acid copolymer (PLGA) is selected from carboxyl-terminated copolymers, and the ratio of lactic acid and glycolic acid monomers in the structure is one of 25:75, 50:50 or 75:25, with a molecular weight of 35,000-57,000.

4. The long-acting epipiperazole in situ gel injection according to claim 1, characterized in that, The gel matrix poloxamer is selected from one or both of poloxamer 407 and poloxamer 188.

5. The long-acting epipiperazole in situ gel injection according to claim 1, characterized in that, The amphiphilic solvent is selected from one or more of N-methyl-2-pyrrolidone, ethanol, dimethylformamide, ethyl benzoate, dimethylacetamide, ethyl acetate, dimethyl sulfoxide, benzyl benzoate, 2-pyrrolidone, benzyl alcohol, and tetrahydrofuran polyethylene glycol ether.

6. The long-acting epipiperazole in situ gel injection according to claim 1, characterized in that, The additives are selected from one or more of glycerol, triacetin, mannitol, methyl heptaate, povidone, glyceryl monostearate, ethyl heptaate, methyl nonanoate, and stearic acid.

7. A method for preparing the long-acting epipiperazole in situ gel injection of claim 1, comprising the following steps: (1) Dissolve ipiperazole in an amphiphilic solvent to prepare solution A; (2) Add polylactic acid-glycolic acid copolymer PLGA and poloxamer to solution A in sequence, mix well to obtain solution B; (3) Add additive to solution B, mix well to obtain solution C; (4) Let solution C stand at room temperature to obtain long-acting epilapiazole in situ gel injection.

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