Bupivacaine multivesicular liposome and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to bupivacaine multivesicular liposome and a preparation method thereof. Comprising the following steps: (a) weighing bupivacaine, DPPG, tricaprylin, DEPC and cholesterol, and dissolving the weighed bupivacaine, DPPG, tricaprylin, DEPC and cholesterol in an organic solvent to serve as an oil phase; (b) continuously homogenizing and mixing the oil phase and the inner water phase through a continuous homogenizer to form W / O primary emulsion; (c) continuously homogenizing and mixing the first-phase W / O primary emulsion and an external water phase through a continuous homogenizer to form W / O / W multiple emulsion; (d) removing the organic solvent from the W / O / W multiple emulsion to obtain a multivesicular liposome suspension I; (e) uniformly mixing the multivesicular liposome suspension I with normal saline, and centrifuging; and (f) re-suspending the centrifuged precipitate in normal saline to obtain the multivesicular liposome. The multi-vesicular liposome is prepared by a continuous high-shear technology, and the process has the advantages of continuous operation, large treatment capacity, short retention time, stable product quality and the like, and is more beneficial to amplified production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to bupivacaine multivesicular liposomes and a preparation method thereof. Background Art

[0002] Bupivacaine is an all-purpose drug that has been shown to be effective for a variety of indications, including local infiltration, peripheral nerve block, sympathetic nerve block, epidural block and caudal block. Bupivacaine is a BCS1 drug with good water solubility but a short half-life. In order to achieve a long-acting sustained-release effect for its injection, it is usually developed into a multivesicular liposome dosage form.

[0003] Multivesicular liposomes (MVLs) are lipid-based drug delivery systems that enable sustained-release properties of drugs with short half-lives. MVLs are structurally different from other types of lipid-based vesicles, such as unilamellar or multilamellar liposomes. MVLs are much larger, typically ranging from 1 to 100 μm, while the MVL of unilamellar vesicles is <100 nm and the MVL of multilamellar vesicles is several hundred nanometers. In addition, compared with the typical concentric bilayer structure observed in multilamellar liposomes, MVLs contain a series of non-concentric polyhedral water chambers separated by lipid membranes. This unique structure gives the liposomes strong rigidity. When one of the vesicles ruptures, the drug is only released from the ruptured vesicle, and the intact vesicles can remain intact, which reduces the drug leakage rate and there is no burst release when the drug is released from the liposomes, achieving controlled drug release over a period of one day to several weeks.

[0004] The preparation of bupivacaine multivesicular liposomes in patents CN 114209654A, CN 110179752A, CN 108158998 B, etc. all use an intermittent high shear mixer to mix the water and oil phases. Intermittent shearing is limited by batch differences during the scale-up process. Different batches lead to different shear mixer parameters. Therefore, intermittent shearing is extremely challenging in the scale-up process. In addition, the multivesicular liposomes prepared by intermittent shearing are prone to rupture and breakage, resulting in poor product stability. In this study, continuous homogenization emulsification technology was used to prepare bupivacaine multivesicular liposomes. Continuous homogenization emulsification technology has the advantages of short mixing time, high yield, and good product quality stability, and is increasingly favored by the industry. Therefore, continuous homogenization emulsification technology is a stable and reliable method for preparing multivesicular liposomes that can be applied to actual commercial scale-up production. Summary of the invention

[0005] In order to solve the above-mentioned technical problems, this application provides the following technical solutions:

[0006] The present invention provides a method for preparing bupivacaine multivesicular liposomes, comprising the following steps:

[0007] S1: continuously and homogeneously mixing an oil phase and an inner aqueous phase to form W / O colostrum; the oil phase is obtained by dissolving bupivacaine, dipalmitoylphosphatidylglycerol (DPPG), tricaprylin, dierucylphosphatidylcholine (DEPC) and cholesterol in an organic solvent;

[0008] S2: continuously and homogeneously mixing the W / O colostrum and the external aqueous phase to form a W / O / W emulsion, and then removing the organic solvent to obtain a multivesicular liposome suspension I;

[0009] S3: The multivesicular liposome suspension I and physiological saline are mixed and then centrifuged to precipitate and resuspend in physiological saline to obtain the bupivacaine multivesicular liposome.

[0010] Preferably, in the oil phase, the concentration of bupivacaine is 4.43-13.3 mg / mL, the concentration of dipalmitoylphosphatidylglycerol is 0.9-2.7 mg / mL, the concentration of tricaprylin is 2-6 mg / mL, the concentration of dierucoyl phosphatidylcholine is 8.2-24.6 mg / mL, and the concentration of cholesterol is 4.7-14.1 mg / mL.

[0011] Preferably, the organic solvent is selected from dichloromethane.

[0012] Preferably, in step S1, the volume ratio of the inner water phase to the oil phase is 1-2:1-5.

[0013] Preferably, in step S1, the volume ratio of W / O colostrum to external water phase is 0.5-1:1-5.

[0014] Preferably, in step S1, the rotation speed of continuous homogenous mixing is 5000-10000 rpm; in step S2, the rotation speed of continuous homogenous mixing is 3000-5000 rpm.

[0015] Preferably, in step S2, the removal method is nitrogen purging.

[0016] Preferably, in steps S1 and S2, the continuous homogenizing mixing is performed using a continuous homogenizer.

[0017] Preferably, the inner aqueous phase is selected from a phosphoric acid aqueous solution, and the outer aqueous phase is selected from a lysine aqueous solution with a concentration of 20-60 mmoL / L.

[0018] Furthermore, the external aqueous phase also contains glucose.

[0019] Specifically, the method for preparing bupivacaine multivesicular liposomes comprises the following steps:

[0020] (a) weighing bupivacaine, DPPG, tricaprylin, DEPC and cholesterol and dissolving them in an organic solvent as an oil phase;

[0021] (b) passing the oil phase and the internal water phase through a continuous homogenizer at a certain flow rate for continuous homogenization and mixing to form W / O colostrum;

[0022] (c) continuously homogenizing and mixing the first phase W / O colostrum with a certain volume of external water phase at a certain flow rate through a continuous homogenizer to form a W / O / W multiple emulsion;

[0023] (d) removing the organic solvent from the W / O / W emulsion to obtain a multivesicular liposome suspension I;

[0024] (e) mixing the multivesicular liposome suspension I with a certain volume of physiological saline and then centrifuging;

[0025] (f) The pellet after centrifugation is resuspended in physiological saline to obtain the final multivesicular liposome suspension.

[0026] The present invention also provides bupivacaine multivesicular liposomes prepared by the above preparation method.

[0027] The technical solution of the present invention has the following advantages over the prior art:

[0028] 1. The multivesicular liposomes are prepared by continuous high shear technology. This process has the advantages of continuous operation, large processing volume, high yield and stable quality of the prepared multivesicular liposomes. It is a stable and reliable method for preparing multivesicular liposomes that can be applied to actual commercial expansion production.

[0029] 2. By studying the volume ratio of colostrum to the second external aqueous phase and the concentration of L-lysine, the concentration of phospholipids in the solution was made appropriate, which increased the encapsulation rate of multivesicular liposomes and improved the stability of multivesicular liposomes. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is a morphological picture of the multivesicular liposomes prepared in Example 8 observed under an optical microscope;

[0031] Figure 2 The in vitro release curves of multivesicular liposomes prepared in Example 1, Example 7, Example 8 and Comparative Example 1;

[0032] Figure 3 This is a diagram showing the effect of the multivesicular liposomes prepared in Example 8 and the bupivacaine hydrochloride solution group on the sensory nerve blocking of rats;

[0033] Figure 4 This is a diagram showing the effect of the multivesicular liposomes prepared in Example 8 and bupivacaine hydrochloride solution on motor nerve blocking in rats. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0035] Example 1

[0036] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purge to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0037] Example 2

[0038] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using a continuous homogenizer at 5000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purge to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0039] Example 3

[0040] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:1 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0041] Example 4

[0042] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as a second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:4 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain a bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0043] Example 5

[0044] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; an aqueous solution containing 20 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0045] Example 6

[0046] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; an aqueous solution containing 60 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purge to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0047] Example 7

[0048] 39.9 mg of bupivacaine, 0.9 mg of DPPG, 2.0 mg of tricaprylin, 8.2 mg of DEPC and 4.7 mg of cholesterol were weighed and dissolved in 3 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; then an aqueous solution with an L-lysine concentration of 40 mmol / L and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0049] Example 8

[0050] 26.61 mg of bupivacaine, 1.8 mg of DPPG, 4.0 mg of tricaprylin, 16.40 mg of DEPC and 9.40 mg of cholesterol were weighed and dissolved in 3 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using a continuous homogenizer to obtain colostrum; then an aqueous solution with an L-lysine concentration of 40 mmol / L and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using a continuous homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0051] Comparative Example 1

[0052] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 5000 rpm using an intermittent homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using an intermittent homogenizer at 3000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0053] Comparative Example 2

[0054] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using an intermittent homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using an intermittent homogenizer at 3000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purge to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0055] Comparative Example 3

[0056] 39.9 mg of bupivacaine was weighed and dissolved in 3 mL of phosphoric acid solution to obtain a first aqueous phase; 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 9 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 10000 rpm using an intermittent homogenizer to obtain colostrum; an aqueous solution containing 40 mmol / L of L-lysine and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using an intermittent homogenizer at 3000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purge to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0057] Comparative Example 4

[0058] 39.9 mg of bupivacaine, 2.7 mg of DPPG, 6.0 mg of tricaprylin, 24.6 mg of DEPC and 14.1 mg of cholesterol were weighed and dissolved in 3 mL of dichloromethane to obtain an oil phase; the first aqueous phase and the same volume of the oil phase were homogenized at 8000 rpm using an intermittent homogenizer to obtain colostrum; then an aqueous solution with an L-lysine concentration of 40 mmol / L and 5% glucose was used as the second aqueous phase, and the colostrum and the second aqueous phase were homogenized at a volume ratio of 1:2.5 using an intermittent homogenizer at 4000 rpm to obtain a double emulsion, and the organic solvent inside was removed by nitrogen purging to obtain bupivacaine multivesicular liposome suspension I. The bupivacaine multivesicular liposome suspension I was injected into the same volume of 0.9% NaCl solution, centrifuged at 3000 rpm for 5 min, the supernatant was discarded, and the bottom precipitate was resuspended in an appropriate volume of 0.9% NaCl solution to obtain the final bupivacaine multivesicular liposome suspension.

[0059] Test Example 1 Particle size and encapsulation efficiency of bupivacaine multivesicular liposomes

[0060] The particle size and encapsulation efficiency of the multivesicular liposomes prepared in the comparative examples and embodiments were measured. The results are shown in Table 1:

[0061] Table 1 Particle size and encapsulation efficiency test results of each comparative example and embodiment

[0062] Group Particle size (μm) Encapsulation rate (%) Comparative Example 1 49.48 43.40 Comparative Example 2 39.99 52.36 Comparative Example 3 22.43 69.58 Comparative Example 4 33.49 60.43 Example 1 28.46 71.35 Example 2 24.24 68.10 Example 3 49.77 66.71 Example 4 22.39 57.31 Example 5 25.36 19.64 Example 6 22.45 45.76 Example 7 33.24 88.95 Example 8 25.42 80.64

[0063] As can be seen from Table 1, compared with the intermittent homogenization technology, the multivesicular liposomes prepared by continuous homogenization have a high encapsulation efficiency and a small particle size that is consistent with the particle size of bupivacaine multivesicular liposomes.

[0064] Test Example 2 Evaluation of in vitro release

[0065] 2 mL of multivesicular liposomes were accurately measured in dialysis bags, and the bubbles in the bags were exhausted and sealed at both ends. The bags were placed in a conical flask containing 50 mL of phosphate buffer release solution. The beaker was placed in a 37°C constant temperature shaker, and the dialysate was taken at 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 h, and fresh release medium of the same volume at the same temperature was added. The drug concentration of the samples was determined by high performance liquid chromatography and the cumulative drug release percentage was calculated. The release curve was drawn with time as the horizontal axis and the cumulative drug release percentage as the vertical axis.

[0066] Test Example 3 In vivo pharmacodynamic evaluation

[0067] Six male SD rats were randomly divided into two groups, with 3 rats in each group, namely the bupivacaine hydrochloride solution group (positive control group) and the bupivacaine multivesicular liposome experimental group. The drug concentrations of the positive control group and the experimental group were both 10 mg / kg. 24 hours before the experiment, the rats' popliteal fossa was shaved in preparation for the experiment on the second day, and then the samples of each group were injected into the popliteal fossa of the rats. After the injection of the samples of each group, the sensory and motor nerve block effects of the rats in each group were evaluated at 0.5h, 1h, 2h, 4h, 8h, 10h, 12h and 24h. Evaluation of sensory nerve block: no reaction at all: 3 points; slight paw retraction: 2 points; pain reaction, but relatively slow: 1 point; rapid paw retraction: 0 points. Evaluation of motor nerve block: complete paralysis of the hind limbs: 2 points; limping but the injected hind limbs cannot move: 1 point; free movement: 0 points. The results are as follows Figure 3 and Figure 4 .

[0068] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing bupivacaine multivesicular liposomes, characterized in that: The following steps are involved: S1: continuously and homogeneously mixing the oil phase and the inner aqueous phase to form W / O colostrum; the oil phase is obtained by dissolving bupivacaine, dipalmitoylphosphatidylglycerol, tricaprylin, dierucylphosphatidylcholine and cholesterol in an organic solvent; S2: continuously and homogeneously mixing the W / O colostrum and the external aqueous phase to form a W / O / W emulsion, and then removing the organic solvent to obtain a multivesicular liposome suspension I; S3: The multivesicular liposome suspension I and physiological saline are mixed and then centrifuged to precipitate and resuspend in physiological saline to obtain the bupivacaine multivesicular liposome.

2. The preparation method according to claim 1, characterized in that In the oil phase, the concentration of bupivacaine is 4.43-13.3 mg / mL, the concentration of dipalmitoylphosphatidylglycerol is 0.9-2.7 mg / mL, the concentration of tricaprylin is 2-6 mg / mL, the concentration of dierucylphosphatidylcholine is 8.2-24.6 mg / mL, and the concentration of cholesterol is 4.7-14.1 mg / mL.

3. The preparation method according to claim 1, characterized in that: The organic solvent is selected from dichloromethane.

4. The preparation method according to claim 1, characterized in that: In the step S1, the volume ratio of the inner water phase to the oil phase is 1-2:1-5.

5. The preparation method according to claim 1, characterized in that: In the step S1, the volume ratio of W / O colostrum to external water phase is 0.5-1:1-5.

6. The preparation method according to claim 1, characterized in that: In the step S1, the rotation speed of the continuous homogenous mixing is 5000-10000 rpm; in the step S2, the rotation speed of the continuous homogenous mixing is 3000-5000 rpm.

7. The preparation method according to claim 1, characterized in that: In the steps S1 and S2, continuous homogenizing and mixing are both performed using a continuous homogenizer.

8. The preparation method according to claim 1, characterized in that: The inner aqueous phase is selected from a phosphoric acid aqueous solution, and the outer aqueous phase is selected from a lysine aqueous solution with a concentration of 20-60 mmoL / L.

9. The preparation method according to claim 8, characterized in that: The external aqueous phase also contains glucose.

10. Bupivacaine multivesicular liposomes prepared by the preparation method according to any one of claims 1 to 9.

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