Olanzapine long-acting injection and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an olanzapine long-acting injection and a preparation method thereof. According to the invention, olanzapine micro powder is dispersed in a medium composed of oil for injection and at least one non-aqueous solvent miscible with water for subcutaneous injection. The combined olanzapine injection can quickly become sticky after subcutaneous injection to form a harder drug storage, so that burst release is reduced, a stable drug release rate is obtained, and different drug release rates can be obtained by adjusting the types and proportions of the oil for injection and at least one non-aqueous solvent miscible with water; the prescription and preparation are simple, and large-scale production is facilitated.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an olanzapine long-acting injection and a preparation method thereof. Background Art

[0002] Olanzapine is an antipsychotic drug that can reduce overactive dopamine and serotonin neurotransmission by specifically blocking dopamine D2 receptors and 5-hydroxytryptamine 2A receptors in the central nervous system, thereby effectively alleviating the core symptoms of schizophrenia. Clinically, olanzapine can be used for: 1) the treatment of schizophrenia. For patients who respond to initial treatment, olanzapine can maintain its clinical effect during maintenance treatment; 2) the treatment of moderate to severe manic episodes. For patients with manic episodes who respond to olanzapine treatment, it can be used to prevent the recurrence of bipolar disorder.

[0003] The currently available commercial preparations of olanzapine include ordinary tablets, orodisintegrating tablets, orodissolving films, capsules, ordinary injections and long-acting injections.

[0004] The oral preparation of olanzapine is used to treat schizophrenia and bipolar disorder. It is well absorbed after administration, reaches the peak blood concentration within 5-8 hours, and food has no effect on absorption. However, it is difficult for psychiatric patients to take medication regularly, which may not only cause fluctuations in drug efficacy and interruption of treatment, but also increase the burden on caregivers.

[0005] The ordinary injection of olanzapine is rapidly absorbed after administration, reaching the peak blood concentration in 15-45 minutes. The peak concentration is about 5 times that of the oral preparation, which is conducive to rapid control of symptoms. Therefore, it is suitable for the treatment of acute agitation associated with schizophrenia and bipolar mania, but not for long-term maintenance treatment.

[0006] Making olanzapine into a long-acting injection can not only provide a stable therapeutic effect for a long time and reduce the risk of relapse, but also effectively improve patient compliance. The currently available olanzapine long-acting injection (ZYPREXARELPREVV) is made by first making olanzapine into insoluble olanzapine pamoate, which is then suspended in water for intramuscular injection. It is injected once every 2 or 4 weeks and is suitable for the treatment of schizophrenia. However, ZYPREXARELPREVV has a risk of sudden release, which may cause post-injection delirium sedation syndrome (PDSS), which manifests as excessive sedation, coma, delirium, and even death. Therefore, patients must stay for at least 3 hours after each injection to ensure the safety of the medication.

[0007] To overcome the shortcomings of ZYPREXARELPREVV, pharmaceutical researchers have also developed various types of olanzapine long-acting injections. CN108289834A and CN116942677A both disclose long-acting injections based on biodegradable polymers, with a PDSS risk of less than 0.07% per injection; however, from their published pharmacokinetic data, the preparation reaches a peak concentration 12-24 hours after injection, and then the concentration continues to decline, and the blood drug concentration is not stable enough. CN103417492A and CN111617043A both disclose olanzapine sustained-release microspheres based on PLGA; CN103417492A does not disclose in vivo pharmacokinetic data, and it is impossible to infer the sustained-release effect after injection; the pharmacokinetic curve disclosed by CN111617043A shows that there is an obvious burst release after injection. CN101106972A discloses a nanoparticle olanzapine long-acting injection containing a surface stabilizer. The results of the pharmacokinetic study in dogs show that the preparation also has an obvious burst release, with a peak time of 4 hours, and the blood drug concentration has dropped significantly after 24 hours. It can be seen that the existing technologies cannot well avoid the burst release phenomenon of olanzapine after injection, and these technologies have problems such as complex formulation, difficult preparation, and difficulty in industrialization. Summary of the invention

[0008] In view of the above-mentioned defects of the prior art, the present invention first provides an olanzapine long-acting injection, comprising olanzapine micropowder and a dispersion medium; wherein the dispersion medium comprises injection oil and at least one non-aqueous solvent miscible with water.

[0009] In some embodiments, based on the total mass of olanzapine long-acting injection as 100%, the mass of the olanzapine micropowder accounts for 20%-40%, the mass of the injection oil accounts for 50%-75%, and the mass of the water-miscible non-aqueous solvent accounts for 1%-15%.

[0010] In some embodiments, the injection oil is selected from at least one of vegetable oil for injection, medium chain fatty acid triglycerides (MCT), benzyl benzoate, benzyl alcohol, and ethyl oleate.

[0011] In some embodiments, the injectable vegetable oil is selected from at least one of injectable soybean oil, sesame oil, olive oil, sesame oil, tea oil, castor oil, corn oil, rapeseed oil, peanut oil, cottonseed oil and sunflower seed oil.

[0012] In some embodiments, the MCT for injection is a saturated straight-chain fatty acid triglyceride containing 6 to 12 carbon atoms.

[0013] In some embodiments, the water-miscible non-aqueous solvent is selected from at least one of glycerol, ethanol, isopropanol, 1,2-propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, N-methylpyrrolidone (NMP), pyrrolidone, dimethyl sulfoxide (DMSO), dimethylacetamide (DMF), 1,3-butanediol, tetrahydrofuran polyglycol ether, and ethyl lactate.

[0014] In some embodiments, the average particle size of the olanzapine micropowder is 0.5 μm-50 μm.

[0015] In some embodiments, the olanzapine long-acting injection further comprises at least one of a pharmaceutically acceptable antibacterial agent, analgesic, and antioxidant.

[0016] In some embodiments, the antibacterial agent is selected from at least one of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, benzyl alcohol, benzoic acid, phenol, cresol, chlorocresol, thimerosal and chlorobutanol;

[0017] The analgesic is selected from at least one of benzyl alcohol, chlorobutanol, lidocaine or procaine;

[0018] The antioxidant is selected from at least one of vitamin E, butylated hydroxyanisole, 2,6-di-tert-butylated hydroxytoluene, vitamin C palmitate, and propyl gallate.

[0019] In some embodiments, the olanzapine long-acting injection further comprises other additives, selected from one or more of sucrose acetate isobutyrate (SAIB), phospholipids, monoolein, diolein and cholesterol. The addition of these additives can further enhance the sustained-release effect while retaining the solidification of the reservoir.

[0020] In another aspect, the present invention provides a method for preparing the olanzapine long-acting injection, comprising the following steps:

[0021] Step S1, preparation of olanzapine micropowder: crushing and sieving olanzapine to obtain olanzapine micropowder, encapsulating the olanzapine micropowder in a first container, and sterilizing;

[0022] Step S2, preparation of dispersion medium: adding the water-miscible non-aqueous solvent to the injection oil, stirring to dissolve, then adding an optional analgesic, antioxidant, antibacterial agent or other additives, stirring until dissolved, filtering to remove impurities, and obtaining the dispersion medium; packaging the dispersion medium in a second container, and sterilizing;

[0023] Before injection, the olanzapine micropowder is mixed evenly with the dispersion medium, and after the bubbles are expelled, subcutaneous injection is performed.

[0024] In some embodiments, in step S1, olanzapine is pulverized using a jet mill and passed through a 120-200 mesh sieve to remove impurities.

[0025] In some embodiments, in step S1, the first container is a screw-cap syringe, which is sterilized using gamma rays.

[0026] In some embodiments, in step S2, impurities are removed by filtering using a 0.45 μm-0.8 μm microporous filter membrane.

[0027] In some embodiments, in step S2, the second container is a vial and is sterilized using gamma rays.

[0028] Technical Effects

[0029] The present invention disperses olanzapine in a medium composed of injection oil and a non-aqueous solvent miscible with water for subcutaneous injection. The olanzapine injection of this specific combination will quickly become viscous after subcutaneous injection to form a relatively hard drug reservoir, thereby reducing burst release and obtaining a stable drug release rate. Different drug release rates can also be obtained by adjusting the type and ratio of the injection oil and the non-aqueous solvent miscible with water; the prescription and preparation are simple, and it is convenient for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is the reservoir form of the olanzapine long-acting injection of the comparative example (a) and the example (b) of the present invention injected into water;

[0031] Figure 2 is the in vitro release curve of the olanzapine long-acting injection of the embodiment of the present invention;

[0032] Figure 3 It is a blood concentration curve diagram after subcutaneous injection of comparative examples and embodiments of the present invention. DETAILED DESCRIPTION

[0033] The following describes several preferred embodiments of the present invention with reference to the drawings in the specification, so that the technical content is clearer and easier to understand. The present invention can be embodied in many different forms of embodiments, and the protection scope of the present invention is not limited to the embodiments mentioned in the text.

[0034] Example 1

[0035] Preparation process of olanzapine long-acting injection:

[0036] Step 1, preparation of olanzapine micropowder: using a jet mill to grind olanzapine powder, passing it through a 120-200 mesh sieve to remove impurities, to prepare olanzapine micropowder with an average particle size d(0.5) of 0.5 μm-50 μm, taking a specified amount of olanzapine micropowder and encapsulating it in a clean and dry screw-mouth syringe, and sterilizing it with gamma rays;

[0037] Step 2, preparation of dispersion medium: add a non-aqueous solvent miscible with water to the oily solvent, stir to dissolve, then add the analgesic, antioxidant, antibacterial agent or other additives, stir until dissolved, filter with a 0.45μm-0.8μm microporous filter membrane to remove impurities, package the dispersion medium in a clean, dry vial, and sterilize with gamma rays.

[0038] Example 2

[0039] How to use olanzapine long-acting injection

[0040] Before injection, draw the dispersion medium into a screw-capped syringe, connect it to the screw-capped syringe containing olanzapine micropowder through a two-way drug distributor, push the piston back and forth more than 40 times until the dispersion medium and olanzapine powder are evenly mixed, draw the mixed liquid into the screw-capped syringe originally containing the dispersion medium, remove the air, put on a 22G needle, and inject.

[0041] Example 3

[0042] Experimental method for needle permeability of olanzapine long-acting injection

[0043] The drug solution was mixed according to the method in Example 2, and the needle was put on to remove air. The pushing rate was set to 1 mm / s, and the maximum resistance to pushing out the olanzapine long-acting injection was measured by a texture analyzer to calculate the maximum pushing pressure (Fmax).

[0044] When Fmax ≥ 250 mPa, it is considered not injectable;

[0045] When 160mPa≤Fmax<250mPa, it is considered difficult to inject;

[0046] When 125mPa≤Fmax<160mPa, it is considered easier to inject;

[0047] When Fmax < 125 mPa, it is considered easy to inject.

[0048] Example 4

[0049] Determination of drug reservoir solidification rate

[0050] Add 4 ml of water to the vial, take the mixed olanzapine long-acting injection, insert the needle under the water surface to push out 0.3 ml of injection, and shake the vial horizontally for a specified time.

[0051] If the drug reservoir as a whole or in part sways back and forth with the water waves, the reservoir is considered unsolidified;

[0052] If the reservoir as a whole does not shake with the water waves, and the reservoir remains in its original shape and does not break when the vial is turned upside down 180°, the reservoir is determined to be solidified.

[0053] Record the curing time and further determine how fast the reservoir cures:

[0054] If the curing time is less than 10 min, it is considered to be fast curing;

[0055] If the curing time is 10-60min, it is considered to be fast curing;

[0056] If the curing time is 1-2h, it is considered to be slow curing;

[0057] If the curing time is 2-4h, it is considered to be slow curing;

[0058] If the curing time is 4h-24h, it is considered to be too slow;

[0059] If the curing time exceeds 24h, it is considered to be uncured.

[0060] Comparative Examples 1-5

[0061] Olanzapine micropowder was suspended in an oily solvent according to the formula listed in Table 1 to prepare an injection. The needle permeability was determined according to the method of Example 3, and the solidification speed was determined according to the method of Example 4. The results are shown in Table 1.

[0062] Table 1

[0063] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Olanzapine 30％ 30％ 30％ 30％ 30％ MCT 70％ tea oil 70％ Soybean Oil 70％ Sesame oil 70％ olive oil 70％ Needle-passing Easy to inject Easy to inject Easy to inject Easy to inject Easy to inject Curing rate Cannot solidify Cannot solidify Cannot solidify Cannot solidify Cannot solidify

[0064] As can be seen from the table above, the reservoir formed by injecting the suspension injection prepared by suspending olanzapine micropowder in an oily solvent into water cannot solidify. The typical reservoir morphology after 24 hours is as follows: Figure 1 -a as shown.

[0065] Embodiment 5-10

[0066] Olanzapine long-acting injection was prepared according to the prescription listed in Table 2, and the preparation method was as shown in Examples 1 and 2. The needle permeability was determined according to the method of Example 3, and the curing speed was determined according to the method of Example 4. The results are shown in Table 2.

[0067] Table 2

[0068] Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Olanzapine 30％ 30％ 30％ 30％ 30％ 30％ MCT 65％ Soybean Oil 65％ Sesame oil 65％ olive oil 65％ tea oil 65％ Benzyl benzoate 65％ Ethanol 5％ 5％ 5％ 5％ 5％ 5％ Needle-passing Easy to inject Easier to inject Easier to inject Easy to inject Easy to inject Easy to inject Curing speed quick Faster quick Faster Faster quick

[0069] As can be seen from the table above, the reservoirs formed by the olanzapine long-acting injection containing 5% ethanol injected into water can solidify quickly. The typical reservoir morphology after 24 hours is as follows: Figure 1 -b as shown.

[0070] Embodiment 11, 12

[0071] Olanzapine long-acting injection was prepared according to the prescription listed in Table 3, and the preparation method was as shown in Examples 1 and 2. The needle permeability was determined according to the method of Example 3, and the curing speed was determined according to the method of Example 4. The results are shown in Table 3.

[0072] Table 3

[0073] Embodiment 11 Example 12 Olanzapine 20％ 40％ MCT 75％ 55％ Ethanol 5％ 5％ Needle-passing Easy to inject Difficult to inject Curing speed slow quick

[0074] Combined with the results of Examples 5, 11, and 12, it can be seen that the content of olanzapine in the prescription has an effect on the curing rate. When the content is 20%, the curing is slow, while when the content is 30%-40%, the curing is fast.

[0075] Examples 13-15

[0076] Olanzapine long-acting injection was prepared according to the prescription listed in Table 4, and the preparation method was as shown in Examples 1 and 2. The needle permeability was determined according to the method of Example 3, and the curing speed was determined according to the method of Example 4. The results are shown in Table 4.

[0077] Table 4

[0078] Embodiment 13 Embodiment 14 Embodiment 15 Olanzapine 33.3％ 33.3％ 33.3％ MCT 65.7％ 62.7％ 59.7％ Ethanol 1％ 4％ 7％ Needle-passing Easy to inject Easy to inject Easy to inject Curing speed slow Faster quick

[0079] It can be seen from the above table that ethanol concentration has a significant effect on the curing rate. As the ethanol content increases, the storage curing rate accelerates.

[0080] Examples 16-21

[0081] Olanzapine long-acting injection was prepared according to the prescription listed in Table 5, and the preparation method was as shown in Examples 1 and 2. The needle permeability was determined according to the method of Example 3, and the curing speed was determined according to the method of Example 4. The results are shown in Table 5.

[0082] Table 5

[0083]

[0084]

[0085] It can be seen from the above table that ethanol and mixed oily solvents can also induce the solidification of the reservoir.

[0086] Examples 22-26

[0087] Olanzapine long-acting injection was prepared according to the prescription listed in Table 6, and the preparation method was as shown in Examples 1 and 2. The needle permeability was determined according to the method of Example 3, and the curing speed was determined according to the method of Example 4. The results are shown in Table 6.

[0088] Table 6

[0089] Embodiment 22 Embodiment 23 Embodiment 24 Embodiment 25 Embodiment 26 Olanzapine 40％ 35％ 30％ 30％ 33.3％ Soybean Oil 50％ 50％ MCT 64％ 30％ 56.7％ Benzyl benzoate 35％ NMP 10％ 15％ Isopropyl alcohol 6％ DMSO 5％ DMF 10％ Needle-passing Easier to inject Easy to inject Easy to inject Easy to inject Easy to inject Curing speed slow Slow Faster Faster Slow

[0090] As can be seen from the above table, hydrophilic solvents such as NMP, isopropanol, DMSO, and DMF can also induce the solidification of the olanzapine reservoir.

[0091] Examples 27-29

[0092] Olanzapine long-acting injection was prepared according to the prescription listed in Table 7, and the preparation method was as shown in Examples 1 and 2. The needle permeability was determined according to the method of Example 3, and the curing speed was determined according to the method of Example 4. The results are shown in Table 7.

[0093] Table 7

[0094]

[0095]

[0096] It can be seen from the above table that after adding excipients such as SAIB, dioleylglycerol, phospholipids, and cholesterol, the reservoir formed by olanzapine long-acting injection when injected into water can still solidify relatively quickly, and the sustained-release effect is further enhanced.

[0097] Experimental Example 1

[0098] Release test:

[0099] The release rate was determined according to the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Rules 0931-"Dissolution and Release Determination Method 2". 500mL of water (containing 0.01% benzalkonium bromide) was used as the release medium, the water bath temperature was 37°C, and the rotation speed was 75rpm. Take the mixed olanzapine long-acting injection, insert the needle under the water surface, push out an appropriate amount of injection (containing about 24mg of olanzapine), and start stirring and timing after the drug reservoir sinks. Take 5mL of samples at 1h, 2h, 3h, 6h, 10h, 24h, and on the 1.5th, 2nd, 3rd, 4th, and 5th days, and replenish fresh release medium of the same temperature and volume in time. The sample was filtered with a 0.45μm microporous membrane, and the filtrate was appropriately diluted and the absorbance was measured at 252nm by UV method, the cumulative release percentage was calculated, and the release curve was drawn.

[0100] Figure 2 The cumulative release curves of olanzapine in Comparative Example 1, Example 5, Example 7, Example 14, Example 21, Example 22 and Example 27 are shown. By comparing the release data, it can be seen that: 1) Since the prescription of Comparative Example 1 does not contain a non-aqueous solvent miscible with water, the early release is fast, reaching about 20% in 10 hours, and the burst release is obvious. 2) Each example prepared after adding a non-aqueous solvent miscible with water can effectively avoid the early burst release, and the release in 10 hours does not exceed 10%.

[0101] Experimental Example 2

[0102] Pharmacokinetic testing:

[0103] Beagle dogs weighing about 15-20kg were taken, half male and half female. The test animals were fasted but not watered for more than 12 hours before the experiment. On the day of the experiment, the olanzapine long-acting injections in Comparative Example 1 and Examples 5 and 14 were subcutaneously injected. The dosage of Comparative Example 1 was 10 mg / kg, the dosage of Example 5 was 10 and 3.3 mg / kg, respectively, and the dosage of Example 14 was 10 mg / kg. Drinking water was allowed 2 hours after administration, and eating was allowed 4 hours later. About 1 ml of blank blood was taken before administration. The injections in Examples 5 and 14 were collected at 1, 3, 6, 10, 24h (1 day), 1.5 days, 2 days, 3 days, 4 days, 5 days, 7 days, 9 days, 11 days, 13 days, 15 days, 17 days, and 19 days after administration. The collected blood samples were placed in sodium heparin anticoagulation tubes, and plasma was centrifuged to separate and the concentration of olanzapine in plasma was determined by HPLC-MS / MS. The pharmacokinetic curve was obtained by plotting the concentration against time (see Figure 3 ), the pharmacokinetic parameters are shown in Table 8 below. Among them, T max C is the peak time; max refers to the peak concentration; AUC 0-t It refers to the area under the drug-time curve from 0 to the last sampling point; MRT refers to the mean residence time in the body; T 0.5 It refers to the terminal elimination half-life.

[0104] Table 8 Pharmacokinetic parameters of olanzapine long-acting injection after subcutaneous injection

[0105]

[0106]

[0107] according to Figure 3 As shown in Table 8, the peak concentration of Comparative Example 1 was reached within 10-24 hours after injection, and the MRT was only about 1.7 days. The concentration after 9 days was lower than the detection limit, which shows that the suspension injection prepared by directly suspending olanzapine in oil has obvious burst release after subcutaneous injection, and the sustained release effect is not good. The long-acting injections described in Examples 5 and 14 reach the peak time after subcutaneous injection in 4-9 days, the peak concentration is significantly reduced, the MRT is significantly prolonged, the blood concentration is very stable within 13 days, and the blood concentration begins to gradually decrease after 13 days. The blood concentration at 19 days is still higher than the quantitative limit, indicating that the olanzapine long-acting injection of the present invention has a good sustained release effect, no early burst release phenomenon, and the drug effect can be maintained for at least 2 weeks.

[0108] Experimental Example 3

[0109] In vivo irritation test:

[0110] The olanzapine long-acting injection in Example 5 was used as the test group, and the blank dispersion medium in this example was used as the control. SD rats were randomly divided into two groups, 3 in each group. The left and right sides of the rat's back waist were shaved, and the injection site was disinfected with 75% alcohol. 0.05 ml (about 75 mg / kg) of olanzapine long-acting injection was subcutaneously injected on the left side, and the corresponding volume of blank dispersion medium was subcutaneously injected on the right side. Observe whether the injection site is red, swollen, or bulging. The rats were killed on the 3rd, 14th, 21st, and 28th days, and the state of the subcutaneous tissue was observed by dissection.

[0111] Swelling, redness, and swelling:

[0112] After subcutaneous injection in the experimental group, obvious bulges were observed at the injection site. Over time, the bulges showed a significant trend of reduction. The volume of the bulges on the 14th day was about 1 / 4 to 1 / 3 of the initial volume, and the bulges had completely disappeared on the 28th day. Obvious bulges were also observed after subcutaneous injection in the medium control group, which dissipated quickly and could no longer be observed on the 3rd day.

[0113] There was no redness or swelling at the injection site in either the control group or the experimental group.

[0114] Anatomical observation:

[0115] In the medium control group, no reservoirs were left on day 3, and the subcutaneous tissue and subcutaneous muscle tissue were normal. In the experimental group, yellow drug reservoirs were observed under the skin on days 3, 14, and 21, and the surrounding tissues were slightly congested, but no degeneration or necrosis was observed. On day 28, the reservoirs disappeared, and the surrounding tissues returned to normal.

[0116] The above results prove that the olanzapine long-acting injection of the present invention can form a drug reservoir at the injection site when injected subcutaneously, the reservoir is degradable, has a relatively mild irritation to the surrounding tissues, can be fully recovered, and has good safety in use.

[0117] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A long-acting olanzapine injection, comprising olanzapine micropowder and a dispersion medium; wherein: The dispersion medium includes injection oil and at least one non-aqueous solvent miscible with water.

2. The olanzapine long-acting injection according to claim 1, wherein: Taking the total mass of olanzapine long-acting injection as 100%, the mass of the olanzapine micropowder accounts for 20%-40%, the mass of the injection oil accounts for 50%-75%, and the mass of the water-miscible non-aqueous solvent accounts for 1%-15%.

3. The olanzapine long-acting injection according to claim 1, wherein: The injection oil is selected from at least one of vegetable oil for injection, medium-chain fatty acid triglycerides, benzyl benzoate, benzyl alcohol, and ethyl oleate.

4. The olanzapine long-acting injection according to claim 3, wherein: The medium-chain fatty acid triglyceride is a saturated straight-chain fatty acid triglyceride containing 6 to 12 carbon atoms.

5. The olanzapine long-acting injection according to claim 1, wherein: The water-miscible non-aqueous solvent is selected from at least one of glycerol, ethanol, isopropanol, 1,2-propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, N-methylpyrrolidone, pyrrolidone, dimethyl sulfoxide, dimethylacetamide, 1,3-butanediol, tetrahydrofuran polyglycol ether, and ethyl lactate.

6. The olanzapine long-acting injection according to claim 1, wherein: The average particle size of the olanzapine micropowder is 0.5 μm-50 μm.

7. The olanzapine long-acting injection according to claim 1, wherein: The olanzapine long-acting injection further comprises at least one of a pharmaceutically acceptable antibacterial agent, analgesic and antioxidant.

8. The olanzapine long-acting injection according to claim 7, wherein: The antibacterial agent is selected from at least one of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, benzyl alcohol, benzoic acid, phenol, cresol, chlorocresol, thimerosal and chlorobutanol; The analgesic is selected from at least one of benzyl alcohol, chlorobutanol, lidocaine or procaine; The antioxidant is selected from at least one of vitamin E, butylated hydroxyanisole, 2,6-di-tert-butylated hydroxytoluene, vitamin C palmitate, and propyl gallate.

9. The olanzapine long-acting injection according to claim 7, wherein: The olanzapine long-acting injection further comprises other additives, and the other additives are selected from one or more of sucrose acetate isobutyrate, phospholipids, monoolein, diolein, and cholesterol.

10. The method for preparing the olanzapine long-acting injection according to any one of claims 1 to 9, comprising the following steps: Step S1, preparation of olanzapine micropowder: crushing and sieving olanzapine to obtain olanzapine micropowder, encapsulating the olanzapine micropowder in a first container, and sterilizing; Step S2, preparation of dispersion medium: adding the water-miscible non-aqueous solvent to the injection oil, stirring to dissolve, then adding an optional analgesic, antioxidant, antibacterial agent or other additives, stirring until dissolved, filtering to remove impurities, and obtaining the dispersion medium; packaging the dispersion medium in a second container, and sterilizing; Before injection, the olanzapine micropowder is mixed evenly with the dispersion medium, and subcutaneous injection is performed after the bubbles are expelled.

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