Bupivacaine microspheres as well as preparation method and application thereof

Abstract

The invention provides bupivacaine microspheres as well as a preparation method and application thereof. The bupivacaine microspheres are prepared from the following raw materials: bupivacaine or a pharmaceutically acceptable salt form thereof, a degradable polymer, an adjuvant and an organic solvent. The molecular weight of the degradable polymer ranges from 5000 Daltons to 25000 Daltons. The bupivacaine microspheres prepared by the invention are moderate in particle size, and the defects of too slow effect, injection pain or too short slow release time and the like can be avoided at the same time; the bupivacaine microspheres prepared by the preparation method disclosed by the invention have relatively high bioavailability and can realize a sustained-release effect of 3-5 days; the preparation method provided by the invention has the advantages of simplicity and convenience in operation, stable process and easiness in industrial production, and the prepared bupivacaine microspheres are high in drug loading capacity.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and relates to bupivacaine microspheres and a preparation method and application thereof. Background Art

[0002] Bupivacaine is an amide local anesthetic frequently used in clinical practice. Due to its long duration of local anesthetic action, obvious separation of sensory and motor blockade, and strong anesthetic efficacy, it is widely used in spinal anesthesia, epidural anesthesia, brachial plexus block, various types of postoperative anesthesia and analgesia, and some long-term and severe cancer pain treatment. The currently marketed bupivacaine injection has a short half-life, and a single injection can only maintain an analgesic effect for about 5 hours, requiring continuous small doses to maintain efficacy. The development of long-acting bupivacaine preparations can not only reduce the number of injections, reduce treatment costs, and alleviate the economic burden on patients, but also reduce the consumption of medical resources and transportation costs, with huge social and economic benefits.

[0003] The long-acting preparations of bupivacaine currently on the market are mainly bupivacaine liposome injections (trade name EXPAREL). A single dose of direct injection can produce analgesia for up to 72 hours. In many clinical trials such as breast augmentation surgery, total knee replacement surgery, and inguinal hernia repair surgery, it has shown many advantages over bupivacaine hydrochloride injection, including reducing the use of opioids, delaying the use of opioids, and improving patient satisfaction. However, the liposomes are multivesicular structures, which have the defects of easy rupture of vesicles, limited embedding rate and drug loading, and poor stability, and the intensity of action is not high. Another long-acting preparation of bupivacaine currently on the market is the bupivacaine gel solution developed by Durect in the United States. The core technology is that sucrose acetate isobutyrate (SAIB), benzyl alcohol and bupivacaine are mixed into a liquid and then injected to form a sustainable release drug reservoir, but the sustainable release can only last for 24 hours.

[0004] Among many long-acting preparations, microsphere preparations have been widely used in the research of long-acting injection forms of various drugs due to their advantages of long sustained-release period and good stability. However, existing microsphere preparations have the following problems: (1) Due to the large particle size, there is a risk of needle blockage during injection, which requires the use of a larger diameter injection needle and causes injection pain to patients; (2) Due to the small particle size, they are easily carried away by body fluids and phagocytosed by macrophages, resulting in the disadvantages of too short a residence time of the microspheres at the injection site and increased systemic absorption of the drug; (3) Due to the small drug loading, small surface pores and less drug distribution, although the drug can achieve long-term effect, the onset of action is too slow.

[0005] Therefore, in the art, it is desired to develop bupivacaine microspheres with suitable particle size, high drug loading, long-acting and rapid onset of action. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide bupivacaine microspheres and a preparation method and application thereof.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides bupivacaine microspheres, wherein the raw materials for preparing the bupivacaine microspheres include bupivacaine or a pharmaceutically acceptable salt thereof, a degradable polymer, an adjuvant, and an organic solvent;

[0009] The molecular weight of the degradable polymer is 5000-25000 Daltons, for example 5000 Daltons, 6000 Daltons, 7000 Daltons, 7500 Daltons, 8000 Daltons, 9000 Daltons, 10000 Daltons, 12000 Daltons, 14000 Daltons, 16000 Daltons, 18000 Daltons, 20000 Daltons, 22000 Daltons, 23000 Daltons, 25000 Daltons, etc.

[0010] The bupivacaine microspheres provided by the present invention have a long-lasting and rapid onset of efficacy and a good local anesthetic effect, and can achieve a local analgesic effect of 2-5 days by adding an adjuvant and limiting the molecular weight of the degradable polymer within a specific range.

[0011] Preferably, the bupivacaine or a pharmaceutically acceptable salt thereof includes any one of bupivacaine base, bupivacaine hydrochloride, and bupivacaine pamoate, or a combination of at least two thereof, more preferably bupivacaine base.

[0012] Preferably, the degradable polymer comprises polylactide (PLA) and / or polylactide-co-glycolide (PLGA).

[0013] Preferably, in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50 to 85:15, such as 50:50, 60:40, 70:30, 80:20, 85:15, etc. The lactide-glycolide copolymer may be terminated by any of carboxyl, ester or hydroxyl groups.

[0014] Preferably, the adjuvant comprises any one of meloxicam, dexamethasone and adrenal hormone, more preferably meloxicam.

[0015] Preferably, the organic solvent includes any one of dichloromethane, chloroform, ethyl acetate, N-methylpyrrolidone, glacial acetic acid, acetone, and methanol, or a combination of at least two thereof, more preferably dichloromethane or glacial acetic acid.

[0016] Preferably, the mass concentration of the degradable polymer in the organic solvent (i.e., degradable polymer / (degradable polymer+organic solvent)*100%) is 1%-35%, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 35%, etc., more preferably 5%-30%. By controlling the mass concentration of the degradable polymer in the organic solvent within a specific range, the prepared bupivacaine microspheres can have a suitable particle size, and defects such as too slow onset, injection pain or too short sustained release time can be avoided at the same time.

[0017] Preferably, the mass ratio of bupivacaine or a pharmaceutically acceptable salt thereof to the degradable polymer is (0.5-1.5):1, for example 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, etc.

[0018] Preferably, the amount of the adjuvant is 0.3wt.%-10wt.% of bupivacaine or a pharmaceutically acceptable salt thereof, for example, 0.3wt.%, 0.5wt.%, 0.6wt.%, 0.8wt.%, 1wt.%, 2wt.%, 3wt.%, 4wt.%, 5wt.%, 6wt.%, 7wt.%, 8wt.%, 9wt.%, 10wt.%, etc.

[0019] Preferably, the raw materials for preparing the bupivacaine microspheres may also include a release regulator.

[0020] Preferably, the average particle size (D50) of the bupivacaine microspheres is 25-50 microns, for example, 25 microns, 30 microns, 35 microns, 40 microns, 45 microns, 50 microns, etc.

[0021] Preferably, the drug loading (DL) of the bupivacaine microspheres is 30%-80%, for example, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, etc.

[0022] Preferably, the release period of the drug in the bupivacaine microspheres is 3-10 days, such as 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, etc., preferably 3-5 days.

[0023] The present invention screens the molecular weight, end group, concentration of the degradable polymer dissolved in an organic phase, etc., and finally achieves the preparation of a bupivacaine microsphere composition with a medium particle size, improved bioavailability and a certain sustained-release effect.

[0024] In a second aspect, the present invention provides a method for preparing bupivacaine microspheres as described in the first aspect, the preparation method comprising the following steps:

[0025] The bupivacaine or its pharmaceutically acceptable salt, a degradable polymer, an adjuvant and an organic solvent in a prescribed amount are mixed to obtain a mixed solution, and the mixed solution is spray-dried or freeze-dried to obtain the bupivacaine microspheres.

[0026] The present invention adopts a spray drying method to prepare bupivacaine microspheres, which has the advantages of simple operation, stable process, and easy industrial production; compared with the preparation of bupivacaine microspheres by an emulsion method, the bupivacaine microspheres prepared by the method provided by the present invention have a higher drug loading amount; the microspheres prepared by the preparation method provided by the present invention have a rounded surface, uniform particle size, and a small amount of raw material drug attached to the surface of the microspheres.

[0027] Preferably, the spray drying is performed by a spray dryer.

[0028] Preferably, the air inlet temperature of the spray dryer is 20-100°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, etc., more preferably 25-65°C.

[0029] Preferably, the atomization pressure of the spray dryer is 0.01-0.5 MPa, for example, 0.01 MPa, 0.03 MPa, 0.05 MPa, 0.08 MPa, 0.1 MPa, 0.2 MPa, 0.3 MPa, 0.4 MPa, 0.5 MPa, etc., more preferably 0.3-0.5 MPa.

[0030] Preferably, the fan speed of the spray dryer is 20-40m 3 / min, for example 20m 3 / min、25m 3 / min、30m 3 / min、35m 3 / min、40m 3 / min, etc.

[0031] Preferably, the nozzle diameter of the spray dryer is 0.5-3.0 mm, for example, 0.5 mm, 0.8 mm, 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3.0 mm, etc.

[0032] In a third aspect, the present invention provides a use of the bupivacaine microspheres as described in the first aspect in analgesic drugs.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The bupivacaine microspheres prepared by the present invention have a moderate particle size, which can avoid defects such as slow onset of action, injection pain, or short sustained release time.

[0035] (2) The bupivacaine microspheres prepared by the present invention have high bioavailability and can achieve a sustained release effect of 3 to 5 days.

[0036] (3) The preparation method provided by the present invention has the advantages of simple operation, stable process, and easy industrial production, and the prepared bupivacaine microspheres have a high drug loading capacity. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is the effect-time graph of bupivacaine microspheres after administration to guinea pigs in Experimental Example 4.

[0038] Figure 2 This is a bar graph showing the change in pain threshold versus time of bupivacaine microspheres in Experimental Example 5.

[0039] Figure 3 This is the pharmacokinetic curve of bupivacaine microspheres in Experimental Example 6. DETAILED DESCRIPTION

[0040] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0041] Example 1

[0042] In this embodiment, bupivacaine microspheres are provided. The raw materials for preparing the bupivacaine microspheres include bupivacaine base, a degradable polymer, an adjuvant meloxicam, and an organic solvent. The specific selection and dosage of each raw material are shown in Table 1.

[0043] The preparation method comprises the following steps:

[0044] The bupivacaine base (BUP), a degradable polymer, an adjuvant and an organic solvent in a formulated amount are mixed to obtain a mixed solution, the mixed solution is spray-dried by a spray dryer, the obtained microspheres are transferred to a vial, and freeze-dried to obtain a bupivacaine microsphere freeze-dried powder;

[0045] Among them, the inlet air temperature, atomization pressure, fan speed and nozzle diameter of the spray dryer are shown in Table 1.

[0046] Examples 2-12, Comparative Examples 1-4

[0047] The difference between Examples 2-12 and Comparative Examples 1-4 and Example 1 is that the specific selection and dosage of the raw materials and the conditions of the preparation method are different, as shown in Tables 1 to 4.

[0048] Table 1

[0049]

[0050]

[0051] Table 2

[0052]

[0053] Table 3

[0054]

[0055]

[0056] Table 4

[0057]

[0058] Comparative Example 5

[0059] The present comparative example provides bupivacaine microspheres, which have the same prescription composition as that of Example 1, except that they are prepared by an oil-in-water emulsion method, and the preparation method comprises the following steps: dissolving bupivacaine base and a degradable polymer in an organic solvent to obtain an oil phase, and homogenizing and emulsifying the resulting oil-in-water emulsion by stirring at 500 rpm to further solidify into microspheres, and repeatedly washing the solidified microspheres with pure water for multiple times to remove residual polyvinyl alcohol, and freeze-drying to obtain bupivacaine microspheres.

[0060] Experimental Example 1

[0061] This experimental example measured the drug loading of the bupivacaine microspheres prepared in Examples 1-12 and Comparative Examples 1-4:

[0062] Accurately weigh bupivacaine to prepare a 0.3 mg / mL bupivacaine solution as a reference solution; accurately weigh 20 mg of the microspheres prepared in Examples 1-12 and Comparative Examples 1-4, place them in a 25 mL volumetric flask, add solvent to dilute to the scale, shake well, take an appropriate amount, centrifuge at 10000 rpm for 15 min, and take the supernatant for high performance liquid chromatography detection.

[0063] Chromatographic conditions: octadecyl bonded silica gel was used as filler (4.6 mm × 250 mm, 5 μm); the detection wavelength was 240 nm;

[0064] The peak retention time and peak area of ​​the chromatogram were recorded, and the amount of bupivacaine in the microspheres was calculated by the external standard method. The drug loading and encapsulation efficiency were calculated according to the following formula.

[0065] Actual drug loading of microspheres (%) = (amount of bupivacaine in microspheres / total weight of microspheres) × 100%;

[0066] Microsphere encapsulation efficiency (%) = (actual drug loading / theoretical drug loading) × 100%.

[0067] The test results are shown in Table 5.

[0068] Table 5

[0069]

[0070]

[0071] As can be seen from the data in Table 5, the bupivacaine microspheres prepared by the preparation method of the present invention can achieve a microsphere encapsulation rate of more than 95%, can achieve customized drug loading, and have a high prescription design space. Comparative Example 2 is not suitable for the preparation method of the present invention because the molecular weight of the degradable polymer is too high and the sample viscosity is too large. Comparative Example 5 The bupivacaine microspheres prepared by the water-in-oil emulsion method have lower drug loading and encapsulation rates than the bupivacaine microspheres prepared by the spray drying method.

[0072] Experimental Example 2

[0073] This experimental example analyzes the particle size of the bupivacaine microspheres prepared in Examples 1-12 and Comparative Examples 1-4:

[0074] Weigh an appropriate amount of bupivacaine microspheres, measure the particle size and particle size distribution according to the method for determination of particle size and particle size distribution (Method 3 of 0982 of Part IV of the 2020 edition of the Chinese Pharmacopoeia), and use a laser particle size analyzer Mastersizer 3000 for determination (the detector shading rate meets the requirements). The specific test results are shown in Tables 1 to 4.

[0075] It can be seen that the D50 particle size of the bupivacaine microspheres prepared by the present invention does not exceed 50 μm, which meets the injection requirements. Comparing the results of Examples 1-12, it can be seen that within the scope of the present invention, the drug loading, the concentration of the degradable polymer, the molecular weight of PLGA, and the effect on the particle size of the microspheres can be regulated within the required range by the process parameters. Comparing the results of Example 1 with Example 3 and Comparative Example 1, the addition of meloxicam does not have a significant effect on the particle size of the microspheres in the present invention. Comparing the results of Example 1 with Comparative Example 5, the bupivacaine microspheres prepared by the oil-in-water emulsion method have a smaller particle size under high shear force.

[0076] Experimental Example 3

[0077] This experimental example conducted an in vitro dissolution test on the bupivacaine microspheres prepared in Examples 1-12 and Comparative Examples 1-4:

[0078] Release medium: pH 7.4 phosphate buffer.

[0079] Accurately weigh 50 mg of bupivacaine microspheres (3 parallel copies) prepared in Examples 1-12 and Comparative Examples 1-4, place in a glass container, accurately add 100 mL of release medium preheated to 37°C ± 0.5°C, immerse in a water bath at 37°C ± 0.5°C, oscillate at a frequency of 100 oscillations per minute, sample at 1h, 4h, 8h, 24h, 48h, 72h, 96h, 120h, respectively, take the supernatant after centrifugation, and enter liquid phase detection. Determination method: HPLC detection is performed with the release medium as a blank solution and a series of concentrations of bupivacaine solution as a reference solution. Calculate the cumulative release, and the specific release results are shown in Tables 1-4.

[0080] The results show that the concentration of the degradable polymer, the molecular weight of the degradable polymer, and the drug loading are within a reasonable range, and the prepared microspheres can achieve a slow release for 3-5 days. Comparing the experimental data of Example 1, Example 3 and Comparative Example 1, the amount of meloxicam added has no significant effect on the in vitro release of the microspheres. Comparing the results of Example 1 and Comparative Example 5, the bupivacaine microspheres prepared by the oil-in-water emulsion method release slightly faster. It is speculated that the slow volatilization of dichloromethane during the curing process causes larger pores to form inside the microspheres, thereby affecting the encapsulation rate and release rate.

[0081] Experimental Example 4

[0082] The local anesthetic effect of bupivacaine microspheres and commercially available bupivacaine hydrochloride injection on guinea pigs was evaluated by acupuncture. Male adult guinea pigs were subjected to local shaving (or depilation) treatment. After continuing to be raised for 12 hours, they were placed on a mouse board and acupunctured on the skin of the shaved part. The animals with negative reactions (no contraction reaction or guinea pig screaming in the skin area of ​​the guinea pig back after acupuncture) were eliminated, and qualified guinea pigs were screened for unified feeding. Take 10 guinea pigs that have passed the screening and randomly divide them into 3 groups, 5 in each group, and the grouping and dosage are as follows: control group (bupivacaine hydrochloride injection, 10 mg / kg), embodiment 1 group (10 mg / kg), comparative example 1 group (10 mg / kg). During the experiment, a needle was used to stimulate the skin of the administration site. If there was a contraction reaction or guinea pig screaming in the skin area at the stimulation site, it was considered a positive reaction, otherwise it was a negative reaction. The number of negative times at a single time point was averaged in each group to obtain the average number of negative times at that time point in each group. The average analgesic reaction rate (effect) was obtained from the average number of negatives. The control group had almost no analgesic effect after 6 hours of administration, and the comparative example 1 had almost no analgesic effect after 3 days of administration. The average analgesic reaction rate of Example 1 remained above 40% after 5 days of administration, which was significantly better than the comparative example 1 and the control group. The effect-time diagram of bupivacaine microspheres after administration in guinea pigs is shown in Figure 2. Figure 1 shown.

[0083] Experimental Example 5

[0084] The bupivacaine microspheres and the solvent attached to the microspheres in Comparative Example 1 and Example 1 and the commercially available bupivacaine hydrochloride injection were used to evaluate the analgesic effect of bupivacaine microspheres on rats with plantar incision. SD rats (SPF grade). They were divided into 4 groups according to their weight, with 6 rats in each group. The rats were longitudinally incised in the middle of the right thigh, about 6-8 mm long, to expose the subcutaneous muscle. The needle was inserted into the muscle next to the sciatic nerve, 0.5 mL of the drug was injected, the muscle was trimmed, and the wound was sutured.

[0085] Detection time points: 15, 30 minutes, and 2, 4, 6, 12, 24, 30, 36, 48, 60, and 72 hours after administration.

[0086] Detection method: Rats were placed on a metal net, each in a separate small compartment. After acclimation for 2 minutes, when the animals were in a quiet and awake state, an electronic pain meter was used to stimulate the skin within 2 mm of the end point of the toe end of the plantar incision of the right hind paw. Each test was performed 3 times with an interval of about 5 seconds. The values ​​were recorded and the average was taken as the mechanical pain threshold. The experimental results are shown in Table 6. The bar graph of the change of pain threshold of bupivacaine microspheres over time is shown in Table 6. Figure 2 shown.

[0087] Table 6

[0088]

[0089] The results showed that: under the current experimental design and administration conditions, no apparent abnormalities were observed in the test substances. In terms of analgesic effect, the microspheres of Example 1 > the microspheres of Comparative Example 1 > the bupivacaine hydrochloride injection.

[0090] The microspheres of Example 1 and Comparative Example 1 have no apparent toxic side effects under the existing administration conditions. The microspheres of Example 1 have significant analgesic effect. After adding meloxicam, the analgesic effect is better than that of the microspheres of Comparative Example 1, and has obvious advantages over bupivacaine hydrochloride injection.

[0091] Experimental Example 6

[0092] The bupivacaine microspheres in comparative example 1 and example 1 were used to evaluate the changes in the blood drug concentration of bupivacaine microspheres in Bama miniature pigs. The groups and dosages were as follows: Example 1 group (9.3 mg / kg), comparative example 1 group (9.3 mg / kg), 3 animals in each group, administration route: single-point subcutaneous injection, administration time: single administration on the first day of the experiment. 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 30h, 36h, 48h, 60h, 72h, 96h after administration, a total of 16 points. After venous blood collection, place it in a labeled EDTA-2K anticoagulant tube. After gently inverting up and down to fully mix the anticoagulant (EDTA-2K) with the blood, immediately place it in wet ice, and centrifuge to separate the plasma within 1 hour after blood collection. The centrifugation conditions are set to 4°C, 6800g, and 6 minutes. The plasma separated after centrifugation was placed in a labeled EP tube and stored in an ultra-low temperature refrigerator (no higher than -60°C) as soon as possible until the sample was analyzed. The remaining plasma after the test was still stored in the ultra-low temperature refrigerator. Figure 3 ) showed that the addition of meloxicam to bupivacaine microspheres significantly improved the bioavailability in pigs.

[0093] The applicant declares that the present invention illustrates the bupivacaine microspheres and the preparation method and application thereof through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of the raw materials selected by the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A bupivacaine microsphere, characterized in that: The raw materials for preparing the bupivacaine microspheres include bupivacaine or a pharmaceutically acceptable salt thereof, a degradable polymer, an adjuvant, and an organic solvent; The molecular weight of the degradable polymer is 5000-25000 Daltons.

2. The bupivacaine microspheres according to claim 1, characterized in that The bupivacaine or a pharmaceutically acceptable salt thereof includes any one of bupivacaine base, bupivacaine hydrochloride, and bupivacaine pamoate, or a combination of at least two thereof, and bupivacaine base is more preferred.

3. The bupivacaine microspheres according to claim 1 or 2, characterized in that: The degradable polymer includes polylactide and / or lactide-glycolide copolymer; Preferably, in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50 to 85:

15.

4. The bupivacaine microspheres according to any one of claims 1 to 3, characterized in that The adjuvant includes any one of meloxicam, dexamethasone and adrenal hormone, more preferably meloxicam.

5. The bupivacaine microspheres according to any one of claims 1 to 4, characterized in that The organic solvent includes any one of dichloromethane, chloroform, ethyl acetate, N-methylpyrrolidone, glacial acetic acid, acetone, and methanol, or a combination of at least two thereof, and more preferably dichloromethane or glacial acetic acid.

6. The bupivacaine microspheres according to any one of claims 1 to 5, characterized in that The mass concentration of the degradable polymer in the organic solvent is 1%-35%, more preferably 5%-30%; Preferably, the mass ratio of bupivacaine or a pharmaceutically acceptable salt thereof to the degradable polymer is (0.5-1.5):1; Preferably, the amount of the adjuvant is 0.3wt.%-10wt.% of bupivacaine or a pharmaceutically acceptable salt thereof.

7. The bupivacaine microspheres according to any one of claims 1 to 6, characterized in that The average particle size of the bupivacaine microspheres is 25-50 microns; Preferably, the drug loading of the bupivacaine microspheres is 30%-80%; Preferably, the release period of the drug in the bupivacaine microspheres is 3-10 days, preferably 3-5 days.

8. A method for preparing bupivacaine microspheres according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: The bupivacaine or its pharmaceutically acceptable salt, a degradable polymer, an adjuvant and an organic solvent in a prescribed amount are mixed to obtain a mixed solution, and the mixed solution is spray-dried or freeze-dried to obtain the bupivacaine microspheres.

9. The preparation method according to claim 8, characterized in that: The spray drying is carried out by a spray dryer; Preferably, the air inlet temperature of the spray dryer is 20-100°C, more preferably 25-65°C; Preferably, the atomization pressure of the spray dryer is 0.01-0.5 MPa, more preferably 0.3-0.5 MPa; Preferably, the fan speed of the spray dryer is 20-40m 3 / min; Preferably, the nozzle diameter of the spray dryer is 0.5-3.0 mm.

10. Use of the bupivacaine microspheres according to any one of claims 1 to 7 in analgesic drugs.

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