Bupivacaine microspheres, and methods of making and using the same

Abstract

The application provides bupivacaine microspheres, a preparation method and application thereof, the preparation raw material of the bupivacaine microspheres comprises bupivacaine or a pharmaceutically acceptable salt type thereof, a degradable polymer, an adjuvant and an organic solvent; the molecular weight of the degradable polymer is 5000-25000 Dalton. The bupivacaine microspheres prepared by the application have moderate particle size, and can simultaneously avoid defects such as slow onset, injection pain or short sustained release time. The bupivacaine microspheres prepared by the application have high bioavailability, and can realize 3-5 days of sustained release effect. The preparation method provided by the application has the advantages of simple operation, stable process, easy industrial production, and high drug loading of the prepared bupivacaine microspheres.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a bupivacaine microsphere as well as a preparation method and application thereof. BACKGROUND

[0002] Bupivacaine is an amide local anesthetic frequently used in clinic. It is widely used in lumbar anesthesia, epidural anesthesia, brachial plexus block, postoperative analgesia and a part of long-term severe cancer pain treatment due to its long-acting, obvious separation of sensory and motor block and strong anesthetic effect. The bupivacaine injection on the market has a short half-life, and only about 5 hours of analgesic effect can be maintained after single injection, so continuous low-dose administration is needed to maintain the effect. The development of long-acting bupivacaine preparations can not only reduce the injection frequency, reduce the treatment cost and the economic burden of patients, but also reduce the consumption of medical resources and transportation costs, and has great social and economic benefits.

[0003] The long-acting bupivacaine preparation currently on the market is mainly bupivacaine liposome injection (trade name EXPAREL). A single dose of direct injection can produce analgesic effect for up to 72 hours. In a number of clinical trials such as breast augmentation surgery, total knee replacement surgery and inguinal hernia repair surgery, it shows many advantages over bupivacaine hydrochloride injection, including reducing the use of opioid drugs, delaying the use of opioid drugs, and improving patient satisfaction. However, the liposome has a multi-vesicular structure, and has the defects of easy vesicle rupture, limited embedding rate and drug loading capacity, and poor stability, and the effect is not strong. Another long-acting bupivacaine preparation on the market is a bupivacaine gel solution developed by Durect Company in the United States. The technical core is that sucrose acetate isobutyrate (SAIB), benzyl alcohol and bupivacaine are blended into a liquid to form a sustained-release drug depot after injection, but the sustained release can only last for 24 hours.

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

[0005] Therefore, in the field, it is desirable to develop a bupivacaine microsphere with a suitable particle size, high drug loading capacity, long-acting and fast onset. SUMMARY

[0006] In view of the deficiencies of the prior art, the present application aims to provide a bupivacaine microsphere, a preparation method and application thereof.

[0007] To achieve the object of the present application, the following technical solutions are adopted:

[0008] In a first aspect, the present application provides a bupivacaine microsphere, wherein the preparation raw material of the bupivacaine microsphere comprises 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 Dalton, for example, 5000 Dalton, 6000 Dalton, 7000 Dalton, 7500 Dalton, 8000 Dalton, 9000 Dalton, 10000 Dalton, 12000 Dalton, 14000 Dalton, 16000 Dalton, 18000 Dalton, 20000 Dalton, 22000 Dalton, 23000 Dalton, 25000 Dalton, etc.

[0010] The bupivacaine microsphere provided by the present application has the advantages that by adding the adjuvant and limiting the molecular weight of the degradable polymer within a specific range, the bupivacaine microsphere has long-lasting and rapid effects, and has good local anesthetic effect, and can achieve 2-5 days of local analgesic effect.

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

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

[0013] Preferably, in the poly(lactide-co-glycolide), the molar ratio of lactide to glycolide is 50:50 to 85:15, for example, 50:50, 60:40, 70:30, 80:20, 85:15, etc. The poly(lactide-co-glycolide) can be any one of carboxyl, ester, or hydroxyl end-capped.

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

[0015] Preferably, the organic solvent comprises any one of dichloromethane, chloroform, ethyl acetate, N-methyl pyrrolidone, glacial acetic acid, acetone, and methanol, or a combination of at least two thereof, and more preferably, the dichloromethane or the 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., and more preferably 5%-30%. By controlling the mass concentration of the degradable polymer in the organic solvent within a certain range, the prepared bupivacaine microspheres can have a suitable particle size, while avoiding defects such as too slow onset, injection pain, or too short sustained release time.

[0017] Preferably, the mass ratio of the bupivacaine or its pharmaceutically acceptable salt type to the degradable polymer is (0.5-1.5):1, such as 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 the bupivacaine or its pharmaceutically acceptable salt type, such as 0.3wt.%, 0.5wt.%, 0.6wt.%, 0.8wt.%, 1wt.%, 2wt.%, 3wt.%, 4wt.%, 5wt.%, 6wt.%, 7wt.%, 8wt.%, 9wt.%, 10wt.%, etc.

[0019] Preferably, the preparation raw material of the bupivacaine microspheres can further include a release regulator.

[0020] Preferably, the average particle size (D50) of the bupivacaine microspheres is 25-50 microns, such as 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%, such as 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., and preferably 3-5 days.

[0023] The present application realizes the preparation of bupivacaine microsphere compositions with medium particle size, improved bioavailability, and certain sustained release effect by screening the molecular weight, end group, and concentration in organic phase of the degradable polymer, etc.

[0024] In a second aspect, the present application provides a preparation method of the bupivacaine microspheres according to the first aspect, comprising the following steps:

[0025] The formula amount of bupivacaine or its pharmaceutically acceptable salt type, degradable polymer, adjuvant and organic solvent are mixed to obtain a mixed solution, and the mixed solution is dried by spray drying or freeze drying to obtain the bupivacaine microspheres.

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

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

[0028] Preferably, the inlet air temperature of the spray dryer is 20-100℃, such as 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, etc., and more preferably 25-65℃.

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

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

[0031] Optionally, the nozzle diameter of the spray dryer is 0.5-3.0mm, such as 0.5mm, 0.8mm, 1mm, 1.5mm, 2mm, 2.5mm, 3.0mm, etc.

[0032] In a third aspect, the present application provides the use of the bupivacaine microspheres according to the first aspect in analgesic drugs.

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

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

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

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

[0037] Figure 1 Figure 4 is an effect-time diagram of the bupivacaine microspheres in experimental example 4 after administration to guinea pigs.

[0038] Figure 2 Figure 5 is a pain threshold-time change bar chart of the bupivacaine microspheres in experimental example 5.

[0039] Figure 3 Figure 6 is a drug metabolism curve of the bupivacaine microspheres in experimental example 6. DETAILED DESCRIPTION

[0040] The technical solutions of the present application will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only to help understand the present application and should not be regarded as specific limitations on the present application.

[0041] Example 1

[0042] In this embodiment, a bupivacaine microsphere is provided, and the preparation raw materials of the bupivacaine microsphere include bupivacaine base, degradable polymer, adjuvant meloxicam, and organic solvent. The specific selection and amount of each preparation raw material are shown in Table 1.

[0043] The preparation method includes the following steps:

[0044] The formula amount of bupivacaine base (BUP), degradable polymer, adjuvant, and organic solvent are mixed to obtain a mixed solution, the mixed solution is sprayed and dried by a spray dryer, the obtained microspheres are transferred to a vial, and freeze-drying is performed to obtain bupivacaine microsphere freeze-dried powder.

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

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

[0047] Examples 2-12 and Comparative Examples 1-4 differ from Example 1 in that the specific selection and amount of preparation raw materials and the conditions of the preparation method are different, as shown in Tables 1-4.

[0048] Table 1

[0049]

[0050]

[0051] Table 2

[0052]

[0053] Table 3

[0054]

[0055]

[0056] Table 4

[0057]

[0058] Comparative Example 5

[0059] This comparative example provides a bupivacaine microsphere, which has the same prescription composition as Example 1, except that it is prepared by an oil-in-water emulsion method, which includes the following steps: dissolving bupivacaine base and degradable polymer in an organic solvent to obtain an oil phase, using a 1 wt% polyvinyl alcohol solution as an external water phase, homogenously emulsifying to form an oil-in-water emulsion, further solidifying the emulsion into microspheres by stirring at 500 rpm, repeatedly washing the solidified microspheres with pure water for multiple times to remove residual polyvinyl alcohol, and lyophilizing to obtain bupivacaine microspheres.

[0060] Experimental Example 1

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

[0062] Bupivacaine was accurately weighed to prepare a 0.3 mg / mL bupivacaine solution as a control solution; 20 mg of the microspheres prepared in Examples 1-12 and Comparative Examples 1-4 were accurately weighed into a 25 mL volumetric flask, diluted to the mark with solvent, shaken well, and an appropriate amount was centrifuged at 10,000 rpm for 15 min, and the supernatant was detected by high performance liquid chromatography.

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

[0064] The chromatogram peak retention time and peak area were recorded, and the amount of bupivacaine in the microspheres was calculated by external standard method, and 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) x 100%;

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

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

[0068] Table 5

[0069]

[0070]

[0071] From the data in Table 5, it can be seen that the bupivacaine microspheres prepared by the preparation method of the present application have a microsphere encapsulation rate of more than 95%, can realize drug loading customization, and have a high prescription design space. The sample viscosity of Comparative Example 2 is too high due to the high molecular weight of the degradable polymer, which is not suitable for the preparation method of the present application. The drug loading and encapsulation rate of the bupivacaine microspheres prepared by the oil-in-water emulsion method in Comparative Example 5 are both lower than those of the bupivacaine microspheres prepared by the spray drying method.

[0072] Experimental Example 2

[0073] In this experimental example, the particle size of the bupivacaine microspheres prepared in Examples 1-12 and Comparative Examples 1-4 was analyzed.

[0074] An appropriate amount of bupivacaine microspheres was weighed, and the particle size and particle size distribution were determined according to the method (Chinese Pharmacopoeia 2020 Edition Part IV General Test 0982 Third Method). The laser particle size analyzer Mastersizer 3000 was used for determination (the detector light shielding rate met the requirements), and the specific test results are shown in Tables 1-4.

[0075] It can be seen that the D50 particle size of the bupivacaine microspheres prepared by the present application is not more than 50 μm, which meets the injection requirements. According to the results of Comparative Examples 1-12, within the scope of the present application, the drug loading, degradable polymer concentration, PLGA molecular weight, and particle size of the microspheres can be controlled to the required range by process parameters. Comparing the results of Comparative 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 application. Comparing the results of Example 1 with Comparative Example 5, the particle size of the bupivacaine microspheres prepared by the oil-in-water emulsion method is smaller under high shear force.

[0076] Experimental Example 3

[0077] In this experimental example, the in vitro dissolution test of the bupivacaine microspheres prepared in Examples 1-12 and Comparative Examples 1-4 was carried out.

[0078] Release medium: pH 7.4 phosphate buffer.

[0079] Accurately weigh 50 mg of bupivacaine microspheres prepared in Examples 1-12 and Comparative Examples 1-4 (three parallel aliquots), place them in a glass container, and accurately add 100 mL of release medium preheated to 37℃±0.5℃. Immerse the container in a water bath at 37℃±0.5℃ and shake at a frequency of 100 times per minute. Samples are taken at 1 h, 4 h, 8 h, 24 h, 48 h, 72 h, 96 h, and 120 h. After centrifugation, the supernatant is collected and analyzed by liquid chromatography. Determination method: HPLC detection is performed using the release medium as a blank solution and bupivacaine solutions of a series of concentrations as reference solutions. The cumulative release rate is calculated, and the specific release results are shown in Tables 1-4.

[0080] The results showed that when the concentration, molecular weight, and drug loading of the biodegradable polymer were within a reasonable range, the prepared microspheres could achieve slow release over 3-5 days. Comparing the experimental data of Example 1, Example 3, and Comparative Example 1, the amount of meloxicam added had 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 released slightly faster, presumably because the slow volatilization of dichloromethane during the curing process led to the formation of larger pores inside the microspheres, thus affecting the encapsulation efficiency and release rate.

[0081] Experimental Example 4

[0082] The local anesthetic effects of bupivacaine microspheres and commercially available bupivacaine hydrochloride injection provided in Example 1 and Comparative Example 1 on guinea pigs were evaluated using the acupuncture method. Male adult guinea pigs underwent local shaving (or hair removal) and were kept in the rearing area for 12 hours. Then, they were placed on a rat board, and the shaved skin was pricked with a needle eight times. Animals showing a negative reaction (no contraction or squealing in the skin area on the back of the guinea pig after acupuncture) were culled. Qualified guinea pigs were then selected for unified rearing. Ten qualified guinea pigs were randomly divided into three groups of five each, with the following grouping and dosage: control group (bupivacaine hydrochloride injection, 10 mg / kg), Example 1 group (10 mg / kg), and Comparative Example 1 group (10 mg / kg). During the experiment, the skin at the treatment site was stimulated with a needle. A contraction or squealing in the stimulated skin area was considered a positive reaction; otherwise, it was considered a negative reaction. The average number of negative reactions at each time point was calculated for each group. The average painless response rate (effect) was calculated from the average number of negative responses. The control group showed almost no analgesic effect 6 hours after administration, and Comparative Example 1 showed almost no analgesic effect 3 days after administration. In Example 1, the average painless response rate remained above 40% 5 days after administration, significantly better than Comparative Example 1 and the control group. The effect-time graph of bupivacaine microspheres in guinea pigs is shown below. Figure 1 As shown.

[0083] Experimental Example 5

[0084] The bupivacaine microspheres in Comparative Example 1 and Example 1, microspheres with solvent and commercially available bupivacaine hydrochloride injection were evaluated for analgesic effect on the incision of the plantar of rats. SD rats (SPF level). According to the weight, the rats were divided into 4 groups, 6 rats in each group. The rats were given a longitudinal incision of about 6-8 mm in the right femoral posterior median, exposing the subcutaneous muscle. The needle was inserted into the muscle beside the sciatic nerve, and 0.5 mL of drug was injected. The muscle was arranged, and the wound was sutured.

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

[0086] Detection method: The rats were placed on a metal mesh, and each rat was placed in a separate small compartment. After the animals were in a calm and awake state for 2 min, the electronic pain tester was used to stimulate the skin within 2 mm of the right hind paw incision endpoint toe end direction, with an interval of about 5 s each time, a total of 3 times and the value was recorded. The mean value was the mechanical pain threshold. The experimental results are shown in Table 6. The bupivacaine microsphere pain threshold-time change bar chart is shown in Figure 2

[0087] Table 6

[0088]

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

[0090] Example 1 and Comparative Example 1 microspheres had no apparent toxic side effects under the existing administration conditions. Example 1 microspheres had a significant analgesic effect. After adding meloxicam, the analgesic effect was better than that of Comparative Example 1 microspheres, and had a significant advantage over bupivacaine hydrochloride injection.

[0091] Experimental Example 6

[0092] ​The bupivacaine microspheres in Comparative Example 1 and Example 1 were used to evaluate the blood concentration change of the bupivacaine microspheres in the Bama miniature pigs. The grouping and dosing were as follows: Example 1 group (9.3 mg / kg), Comparative Example 1 group (9.3 mg / kg), each group using 3 animals, the administration route: single point subcutaneous injection, the administration time: single administration on the first day of the test. After administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 30 h, 36 h, 48 h, 60 h, 72 h, 96 h, a total of 16 points. The venous blood was placed in a labeled EDTA-2K anticoagulant tube. After the anticoagulant (EDTA-2K) was mixed with the blood, it was immediately placed in wet ice, and the plasma was separated by centrifugation within 1 hour after blood sampling, with the centrifugation conditions set as 4°C, 6800g, 6 minutes. The plasma separated after centrifugation was placed in a labeled EP tube, and was stored in an ultra-low temperature freezer (not higher than -60°C) as soon as possible until sample analysis. The remaining plasma after detection was still stored in the ultra-low temperature freezer. The experimental results Figure 3 ) showed that the addition of meloxicam to the bupivacaine microspheres significantly improved the bioavailability in pigs.

[0093] The applicant declares that the bupivacaine microspheres, the preparation method and the application of the present application are illustrated by the above examples, but the present application is not limited to the above examples, that is, it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of the selected materials of the present application, addition of auxiliary ingredients, selection of specific methods, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. A bupivacaine microsphere, characterized by, The preparation raw material of the bupivacaine microspheres comprises bupivacaine or a pharmaceutically acceptable salt form thereof, a degradable polymer, an adjuvant, and an organic solvent; The average particle size of the bupivacaine microspheres is 25-40 microns; The adjuvant is meloxicam; The amount of the adjuvant is 0.3wt.%-10wt.% of bupivacaine or a pharmaceutically acceptable salt form thereof; The mass ratio of bupivacaine or a pharmaceutically acceptable salt form thereof to the degradable polymer is (0.5-1.5):1; The molecular weight of the degradable polymer is 5000-16000 Dalton; The mass concentration of the degradable polymer in the organic solvent is 5%-30%; The degradable polymer is polylactide and / or polylactide-co-glycolide; In the polylactide-co-glycolide, the molar ratio of lactide to glycolide is 50:50 to 85:15; The preparation method of the bupivacaine microspheres comprises the following steps: The formula amount of bupivacaine or a pharmaceutically acceptable salt form thereof, a degradable polymer, an adjuvant, and an organic solvent are mixed to obtain a mixed solution, and the mixed solution is subjected to spray drying and freeze drying to obtain the bupivacaine microspheres.

2. The bupivacaine microspheres of claim 1, wherein, The bupivacaine or a pharmaceutically acceptable salt form thereof comprises any one or a combination of at least two of bupivacaine base, bupivacaine hydrochloride, and bupivacaine pamoate.

3. The bupivacaine microspheres of claim 2, wherein, The pharmaceutically acceptable salt form of bupivacaine is bupivacaine base.

4. The bupivacaine microspheres of claim 1, wherein, The organic solvent comprises any one or a combination of at least two of dichloromethane, chloroform, ethyl acetate, N-methyl pyrrolidone, glacial acetic acid, acetone, and methanol.

5. The bupivacaine microspheres of claim 4, wherein, The organic solvent is dichloromethane or glacial acetic acid.

6. The bupivacaine microspheres of claim 1, wherein, The drug loading amount of the bupivacaine microspheres is 30%-80%.

7. The bupivacaine microspheres of claim 1, wherein, The drug release period of the bupivacaine microspheres is 3-10 days.

8. The bupivacaine microspheres of claim 7, wherein, The drug release period of the bupivacaine microspheres is 3-5 days.

9. A method of preparing the bupivacaine microspheres according to any one of claims 1 to 8, characterized in that, The preparation method comprises the following steps: The formula amount of bupivacaine or a pharmaceutically acceptable salt form thereof, a degradable polymer, an adjuvant, and an organic solvent are mixed to obtain a mixed solution, and the mixed solution is subjected to spray drying and freeze drying to obtain the bupivacaine microspheres.

10. The method of claim 9, wherein, The spray drying is performed by a spray dryer.

11. The method of claim 10, wherein, The inlet air temperature of the spray dryer is 20-100℃.

12. The method of claim 11, wherein, The inlet air temperature of the spray dryer is 25-65℃.

13. The preparation method according to claim 10, characterized in that, The atomization pressure of the spray dryer is 0.01-0.5 MPa.

14. The method of claim 13, wherein, The atomization pressure of the spray dryer is 0.3-0.5 MPa.

15. The preparation method according to claim 10, characterized in that, The fan speed of the spray dryer is 20-40 m 3 / min.

16. The method of claim 10, wherein, The nozzle diameter of the spray dryer is 0.5-3.0 mm.

17. Use of the bupivacaine microspheres according to any one of claims 1-8 in the preparation of an analgesic drug.

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