Levobupivacaine liposome long-acting injection as well as preparation process and application thereof

Abstract

The invention belongs to the field of analgesic drugs, and relates to a levobupivacaine liposome long-acting injection as well as a preparation process and application thereof. The injection comprises the following components: levobupivacaine, neutral phospholipid, charged phospholipid, cholesterol, tricaprylin, lysine, glucose and normal saline. Components are optimized, levobupivacaine and lipid components form a lipid phase in the preparation process, then the lipid phase is mixed with an internal water phase, and the stability of primary emulsion is better facilitated by combining the synergistic improvement of the components and the process; meanwhile, lysine and glucose are added into the external water phase, and the dosage is optimized, so that a stable charge system is formed, the generated liposome is more stable, and aggregation and flocculation of small balls are avoided; the encapsulation efficiency of the final product is 90% or above, D50 is 25-40 microns, the in-vivo half-life period is prolonged by 7 times compared with that of a common injection, MRT is prolonged by 6 times, the injection is stably released in SD rats, long-acting slow release of 48 h is achieved, and the injection has wide application prospects in the field of analgesic drugs.

Description

Technical Field

[0001] This invention belongs to the field of analgesic drugs, specifically relating to levobupivacaine liposome long-acting injection, its preparation process, and its uses. Background Technology

[0002] Postoperative pain often triggers a stress response in patients, which in severe cases can lead to disturbances in gastrointestinal, cardiopulmonary, coagulation, and endocrine metabolic functions, affecting postoperative recovery and causing both physical pain and psychological burden. Clinically, the duration of postoperative pain ranges from several days to two months, or even longer, depending on the type of surgery, the extent of surgical trauma, and the patient's pain tolerance. Most patients experience intense pain for 2-3 days after surgery, generally requiring multiple doses of medication to alleviate postoperative pain. Therefore, developing a long-acting formulation to address the drawbacks of multiple doses is both necessary and valuable.

[0003] Bupivacaine, an amide-type local anesthetic, is a widely used surgical local anesthetic and postoperative analgesic in clinical practice. However, the conventional dosage of bupivacaine is 0.5%, and a single dose provides local analgesia for less than 7 hours. This insufficient duration of action necessitates continuous administration via other methods to meet the needs of sustained clinical treatment. Levobupivacaine, the levorotatory isomer of bupivacaine, is primarily used clinically for anesthesia. Its anesthetic efficacy is similar to bupivacaine, but its neurotoxicity and cardiotoxicity are significantly reduced, making it safer to use. Therefore, the development of long-acting sustained-release formulations of levobupivacaine for postoperative analgesia is a key research direction.

[0004] The chemical name of levobupivacaine is S-(-)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide, and its structural formula is shown in Formula 1:

[0005]

[0006] Long-acting liposomes are non-concentric honeycomb-like formulations composed of multiple chambers compressed together, resembling spherical shapes. They accumulate at the injection site, and the chambers gradually rupture to release the encapsulated drug, achieving excellent sustained-release properties. This enhances the drug-carrying capacity of traditional liposomal drugs and prolongs drug release time. Multi-capsule liposomes are prepared by mixing a drug-containing organic phase with an inner aqueous phase to obtain a first-phase W / O emulsion. This first-phase W / O is then dispersed in an outer aqueous phase to obtain a relatively stable dispersed W / O / W emulsion. Rapid removal of the organic solvent forms a multi-capsule structure. As the organic solvent is gradually removed, the capsule hardness gradually increases, ultimately forming a stable multi-capsule liposome. Therefore, forming a stable W / O / W emulsion is a key step in multi-capsule formation. However, improper process control during solution preparation can easily lead to phospholipid breakage, aggregation, and the formation of flocculent substances that float in the solution, which is a technical problem that urgently needs to be solved. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a method for preparing a long-acting levobupivacaine liposome injection, resulting in a stable, long-lasting analgesic levobupivacaine liposome injection with a 7-fold extended in vivo half-life, a 6.0-fold extended median time (MRT), and stable in vivo drug release, achieving a 48-hour sustained-release effect, thereby expanding its indications. The levobupivacaine long-acting liposome injection provided by this invention not only has high encapsulation efficiency and good stability but also possesses a long-lasting effect. Furthermore, this invention also provides a preparation process for the levobupivacaine liposome long-acting injection and its application in postoperative analgesia. Due to its good stability and long-lasting effect, it can reduce the number of injections, improve patient compliance, expand the indications for levobupivacaine, and facilitate clinical application, better serving patients and possessing promising application prospects.

[0008] To overcome the shortcomings of the prior art, the present invention provides the following technical solution:

[0009] The first aspect of the present invention provides a long-acting levobupivacaine liposome injection solution, which is composed of the following components: levobupivacaine, neutral phospholipids, charged phospholipids, cholesterol, tricaprylic acid lysine, glucose and physiological saline.

[0010] Furthermore, each 1000 mL of the levobupivacaine long-acting liposome injection solution contains the following components and dosages:

[0011] Levobupivacaine 11-16g, neutral phospholipids 6-10g, the charged phospholipids being negatively charged phospholipids 0.5-3g, cholesterol 2-6g, tricaprylic acid glyceride 1-5g, lysine 46-60g, glucose 288-300g, and the remainder being physiological saline.

[0012] Furthermore, the neutral phospholipid is selected from any one or more of the following: tricaprylic acid glyceride, egg yolk lecithin, soybean lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, and dioleoyl phosphatidylcholine.

[0013] Furthermore, the negatively charged phospholipid is selected from any one or more of dipalmitoylphosphatidylglycerol, phosphatidylethanolamine, myristoylphosphatidylglycerol, distearylphosphatidylglycerol, and distearylphosphatidyl acid.

[0014] Furthermore, the levobupivacaine long-acting liposome injection of the present invention is a liposome suspension injection.

[0015] A second aspect of the present invention provides a method for preparing a long-acting levobupivacaine liposome injection, comprising the following steps:

[0016] S1: An aqueous solution of inorganic acid is used as the internal aqueous phase; the concentration of the aqueous solution of inorganic acid is 0.25 mol / L to 0.30 mol / L;

[0017] Furthermore, in step S1, the inorganic acid aqueous solution is a phosphoric acid solution with a concentration of 0.27 mol / L to 0.28 mol / L;

[0018] S2: Levobupivacaine, neutral phospholipids, negatively charged phospholipids, cholesterol and triglycerides are dissolved in an organic solvent according to the mass ratio, and then dissolved by water bath or ultrasonic treatment to obtain the lipid phase after dissolution;

[0019] Furthermore, the organic solvent mentioned in step S2 includes any one or more of anhydrous ethanol, chloroform, dichloromethane, and methanol; the temperature during the water bath treatment in step S2 is 25±1℃.

[0020] S3: Add lysine and glucose to water according to the mass ratio, stir and dissolve at room temperature to obtain the external aqueous phase;

[0021] Furthermore, in step S3, the water is water for injection; the mass fractions of lysine and glucose in the external aqueous phase are controlled to be 0.4%-0.8% (w / w) and 3.5%-5.5% (w / w), respectively.

[0022] S4: The internal aqueous phase in S1 is mixed with the lipid phase in S2 and homogenized and sheared to form a primary emulsion; then the external aqueous phase in S3 is divided into two parts, denoted as external aqueous phase A and external aqueous phase B respectively; the primary emulsion is first mixed with external aqueous phase A and homogenized and sheared a second time to form a secondary emulsion; then the secondary emulsion is mixed evenly with external aqueous phase B, and the organic solvent is removed by aeration to obtain crude liposomes, which are long-acting liposome intermediates;

[0023] Furthermore, in S4, the volume ratio of the lipid phase, the inner aqueous phase, the outer aqueous phase A, and the outer aqueous phase B is 1:0.8~1.2:2~6:12~19; in the process of forming the primary emulsion through homogenization shearing, the homogenization shearing temperature is 20℃~25℃, the linear velocity is 6-10m / s, and the time is 10-15min; the linear velocity of the second homogenization shearing is 2-5m / s, the temperature is 20℃~25℃, and the time is 60-300s; the gas used for removing organic solvents through aeration is nitrogen.

[0024] S5: Add the long-acting liposome intermediate from S4 to physiological saline, and finally concentrate it by tangential flow ultrafiltration to obtain the concentrate, which is the levobupivacaine long-acting liposome injection solution.

[0025] Furthermore, in S5, the volume ratio of the long-acting liposome intermediate to physiological saline is 1:6-8; the ultrafiltration column used for ultrafiltration concentration is an mPES hollow fiber membrane column with a pore size of 750KD; the particle size D50 of the levobupivacaine long-acting liposome injection is 25-40um, and the appearance is a white suspension; the encapsulation rate of the levobupivacaine long-acting liposome injection is greater than 90%, and it is stable during storage.

[0026] A third aspect of the present invention provides the application of levobupivacaine long-acting liposome injection in the preparation of analgesic drugs.

[0027] Beneficial effects:

[0028] The following technical effects are achieved by adopting the technical solution of the present invention:

[0029] This invention optimizes the composition and controls the dosage. In the preparation process, the drug levobupivacaine is first mixed with lipid components to form a lipid phase, and then mixed with the inner aqueous phase. The synergistic improvement of composition, dosage and process enhances the stability of the colostrum. At the same time, this invention adds lysine and glucose to the outer aqueous phase and strictly controls the amount added, thereby forming a stable charge system, which improves the stability of the liposome microsphere formation process, making the generated liposomes more stable and obtaining a stable liposome suspension.

[0030] This invention employs a reasonable raw material formulation ratio and a simple preparation process to prepare a long-acting liposome injection of the drug levobupivacaine for the first time. It has good encapsulation efficiency and release rate; its in vivo half-life is extended by 7 times, MRT is extended by 6.0 times, and the drug release in vivo is stable, achieving a long-acting sustained-release effect of 48 hours.

[0031] This invention presents a production process with good reproducibility and high yield, providing a stable and reliable method for preparing levobupivacaine long-acting liposome injection that can be applied to practical commercial-scale production. This formulation, process, and preparation method solve the problems of the drug's short half-life and the need for multiple injections in solution formulations, significantly improving the long-acting sustained-release effect, reducing the number of injections, increasing clinical affordability, and lowering patient medical costs, thus possessing broad clinical application value. Attached Figure Description

[0032] Figure 1 The in vivo drug release curves after administration of the injection group and the liposome group are shown.

[0033] Figure 2 The results show the mechanical foot reflex threshold (MWT) of rats after drug administration. Detailed Implementation

[0034] The present invention will be further described below with reference to specific embodiments. Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and implementations of the present invention.

[0035] It should be understood that the terminology used herein is merely for describing particular embodiments and is not intended to limit the invention. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0036] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, which will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This specification and embodiments are merely exemplary; reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0037] Example 1:

[0038] A long-acting levobupivacaine liposome injection, with the following original and excipient ratio: each 1000 mL of long-acting levobupivacaine liposome injection contains the following components: levobupivacaine 15.4 g, neutral phospholipids 9.8 g, negatively charged phospholipids 1.4 g, cholesterol 4.2 g, caprylic acid glyceride 2.8 g, lysine 46 g, and glucose 288 g;

[0039] The preparation process of levobupivacaine long-acting liposome injection includes the following steps:

[0040] S1: Use a 0.25 mol / L phosphoric acid solution as the internal aqueous phase;

[0041] S2: The analgesic drug levobupivacaine, neutral phospholipids, negatively charged phospholipids, cholesterol and triglycerides were dissolved in 400 mL of organic solvent (methanol: dichloromethane = 1:99, v / v) according to the above mass ratio, and dissolved in a water bath at 25 °C to obtain the lipid phase;

[0042] S3: Add the above-mentioned lysine and glucose to 7000 mL of water for injection according to the above mass ratio, stir and dissolve at room temperature to obtain an external aqueous phase;

[0043] S4: The internal aqueous phase and organic phase are mixed at a volume ratio of 1:1 and sheared at 7 m / s for 12 min at 25 °C to form a primary emulsion; then the external aqueous phase in S3 is divided into two parts, labeled as external aqueous phase A (800 mL) and external aqueous phase B (6200 mL); the primary emulsion is first mixed with external aqueous phase A (800 mL) and sheared at 3 m / s for 120 s at 25 °C to form a secondary emulsion; then the secondary emulsion is mixed evenly with external aqueous phase B (6200 mL) to form an emulsion, and N2 is bubbled into the emulsion from the bottom to make the emulsion turbulent. After removing the organic solvent by aeration, the long-acting levobupivacaine liposome intermediate is obtained;

[0044] S5: The levobupivacaine long-acting liposome intermediate was diluted with 6 times its volume of physiological saline (0.9% sodium chloride) and concentrated by tangential flow ultrafiltration (the ultrafiltration column used for ultrafiltration concentration was an mPES hollow fiber membrane column with a pore size of 750KD) to obtain levobupivacaine long-acting liposome injection solution with a particle size D50 of 25.95um, a white suspension appearance, and an encapsulation rate of 97%.

[0045] Example 2:

[0046] A levobupivacaine polycystic liposome injection, with the following ratio of raw material and excipient: each 1000 mL of levobupivacaine long-acting liposome injection contains the following components: levobupivacaine 16 g, neutral phospholipids 8 g, negatively charged phospholipids 2.5 g, cholesterol 4 g, caprylic acid glyceride 2 g, lysine 50 g, and glucose 300 g.

[0047] The preparation process of levobupivacaine long-acting liposome injection includes the following steps:

[0048] S1: Use a 0.275 mol / L phosphoric acid solution as the internal aqueous phase;

[0049] S2: Dissolve the analgesic drug levobupivacaine, neutral phospholipids, negatively charged phospholipids, cholesterol and triglycerides in 500 mL of organic solvent (methanol: dichloromethane = 1:124, v / v) according to the above mass ratio, and dissolve in a water bath at 25 °C to obtain the lipid phase;

[0050] S3: Add the above-mentioned lysine and glucose to 8000 mL of water for injection according to the above mass ratio, stir and dissolve at room temperature to obtain an external aqueous phase;

[0051] S4: The internal aqueous phase and organic phase are mixed at a volume ratio of 1:1 and sheared at 10 m / s for 10 min at 25 °C to form a primary emulsion; then the external aqueous phase in S3 is divided into two parts, labeled as external aqueous phase A (1600 mL) and external aqueous phase B (6400 mL); the primary emulsion is first mixed with external aqueous phase A (1600 mL) and sheared at 4 m / s for 60 s at 25 °C to form a secondary emulsion; then the secondary emulsion is mixed evenly with external aqueous phase B (6400 mL) to form an emulsion, and N2 is bubbled into the emulsion from the bottom to make the emulsion turbulent. After removing the organic solvent by aeration, the long-acting levobupivacaine liposome intermediate is obtained;

[0052] S5: The levobupivacaine long-acting liposome intermediate was diluted with 8 times its volume of physiological saline (0.9% sodium chloride) and concentrated by tangential flow ultrafiltration (the ultrafiltration column used for ultrafiltration concentration was an mPES hollow fiber membrane column with a pore size of 750KD) to obtain levobupivacaine long-acting liposome injection solution with a particle size D50 of 29.88um, a white suspension in appearance, and an encapsulation rate of 98%.

[0053] Example 3:

[0054] A levobupivacaine polycystic liposome injection, with the following ratio of raw material and excipient: each 1000 mL of levobupivacaine long-acting liposome injection contains the following components: levobupivacaine 13g, neutral phospholipids 9g, negatively charged phospholipids 2g, cholesterol 3g, tricaprylic acid glyceride 3g, lysine 60g, and glucose 300g.

[0055] The preparation process of levobupivacaine long-acting liposome injection includes the following steps:

[0056] S1: Use a 0.275 mol / L phosphoric acid solution as the internal aqueous phase;

[0057] S2: Dissolve the analgesic drug levobupivacaine, neutral phospholipids, negatively charged phospholipids, cholesterol and trioctyl glycerol in 500 mL of dichloromethane according to the above mass ratio, and dissolve in a water bath at 25°C to obtain the lipid phase.

[0058] S3: Add the above-mentioned lysine and glucose to 8000 mL of water for injection according to the above mass ratio, stir and dissolve at room temperature to obtain an external aqueous phase;

[0059] S4: The internal aqueous phase and organic phase were mixed at a volume ratio of 1:1.2 and sheared at 25℃ for 6m / s for 15min to form a primary emulsion; then the external aqueous phase in S3 was divided into two parts, labeled as external aqueous phase A (880mL) and external aqueous phase B (7120mL); the primary emulsion was first mixed with external aqueous phase A (880mL) and sheared at 25℃ for 2m / s for 300s to form a secondary emulsion; then the secondary emulsion was mixed evenly with external aqueous phase B (7120mL) to form an emulsion, and N2 was bubbled into the emulsion from the bottom to make the emulsion turbulent. After removing the organic solvent by aeration, the long-acting levobupivacaine liposome intermediate was obtained.

[0060] S5: The levobupivacaine long-acting liposome intermediate was diluted with 6 times its volume of physiological saline (0.9% sodium chloride) and concentrated by tangential flow ultrafiltration (the ultrafiltration column used for ultrafiltration concentration was an mPES hollow fiber membrane column with a pore size of 750KD) to obtain levobupivacaine long-acting liposome injection solution with a particle size D50 of 32.58um, a white suspension appearance, and an encapsulation rate of 95%.

[0061] The levobupivacaine long-acting liposome injections prepared in Examples 1-3 contained levobupivacaine at a concentration of 13-18 mg / mL. Subsequent experiments were conducted using the product prepared in Example 1 (levobupivacaine long-acting liposome injection).

[0062] Example 4:

[0063] The product prepared in Example 1 (levobupivacaine long-acting liposome injection) was used for testing experiments; and levobupivacaine hydrochloride injection, a commercially available reagent, was used. (Zhuhai Rundu Pharmaceutical Co., Ltd.) is used as a comparison;

[0064] Pharmacokinetic Model: Ten healthy male SD rats aged 7-8 weeks and weighing 180-200g were selected and housed at 18-26℃ and 30-70% relative humidity for 3-5 days to allow them to acclimatize. The SD rats were then divided into two groups, receiving subcutaneous injections of 10 mg / kg levobupivacaine hydrochloride injection (injection group) and levobupivacaine long-acting liposome injection (liposome group), respectively. Blood samples of 0.2 mL were collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 10, 16, 24, 48, and 72 hours post-injection. The plasma levobupivacaine concentration was measured, and pharmacokinetic data were calculated. The results are as follows:

[0065] Table 1. Blood drug concentrations in SD rats after drug administration in the two groups.

[0066]

[0067] Table 2 Pharmacokinetic Parameters

[0068]

[0069] Figure 1 The in vivo drug release curves of the injection group and the liposome group after administration are shown in Table 1-2. As can be seen from the table, the in vivo half-life of the injection prepared in this invention is 7 times longer than that of ordinary injection, and the MRT (Mean Residence Time) is 6.0 times longer. The drug release curve of the long-acting liposome injection of levobupivacaine in SD rats shows that its release is stable and achieves a long-acting sustained-release effect of 48 hours.

[0070] Example 5:

[0071] The product prepared in Example 1 (levobupivacaine long-acting liposome injection) was used for testing experiments;

[0072] Drug efficacy model: Forty healthy male SD rats aged 7-8 weeks and weighing 180-200g were selected and housed at 18-26℃ and 30-70% relative humidity for 3-5 days to allow the SD rats to acclimatize to the environment. The SD rats were then randomly assigned to 5 groups:

[0073] The normal group (G1), without any trauma, did not receive the injection;

[0074] In the model group (G2), after the scratch, physiological saline was injected near the wound at a dose of 10 mg / kg.

[0075] In the low-dose group (G3), after the scratch, a low dose of levobupivacaine liposome injection was injected near the wound at a dose of 10 mg / kg.

[0076] In the high-dose group (G4), after the scratch, a high dose of levobupivacaine liposome injection was injected near the wound at a dose of 30 mg / kg.

[0077] In the positive drug group (G5), after the laceration, levobupivacaine injection was administered near the wound. Zhuhai Rundu Pharmaceutical Co., Ltd.), the injection dose is 10mg / kg;

[0078] The drugs were administered once daily, immediately after the model was created. The mechanical foot reflex threshold (MWT) of the rat's hind paw was measured one day before model creation and at 0h, 2h, 4h, 6h, 12h, 24h, 36h, 48h, 60h, 72h, day 4, day 5, day 6, day 7, day 8, day 9, and day 10 after drug administration. The results are as follows: Figure 2 .

[0079] The results showed that the levobupivacaine liposome injection had a significant analgesic effect, and the effect was better with increasing dosage. This indicates that the prepared levobupivacaine liposome injection has a good analgesic effect.

[0080] Note: The above embodiments are only used to illustrate the present invention and are not intended to limit the technical solutions described in the present invention. Therefore, although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the present invention. All technical solutions and improvements that do not depart from the spirit and scope of the present invention should be covered within the scope of the claims of the present invention.

Claims

1. A long-acting levobupivacaine liposome injection solution, characterized in that, Composed of the following components Composition: Levobupivacaine, neutral phospholipids, charged phospholipids, cholesterol, tricaprylic acid glyceride lysine, glucose, and physiological saline.

2. The levobupivacaine long-acting liposome injection solution according to claim 1, characterized in that, The aforementioned long-acting levobupivacaine liposome injection is a liposome suspension injection. Each 1000 mL of levobupivacaine long-acting liposome injection contains the following components and dosages: Levobupivacaine 11-16g, neutral phospholipids 6-10g, the charged phospholipids being negatively charged phospholipids 0.5-3g, cholesterol 2-6g, tricaprylic acid glyceride 1-5g, lysine 46-60g, glucose 288-300g, and the remainder being physiological saline.

3. The levobupivacaine long-acting liposome injection solution according to claim 1, characterized in that, The neutral phospholipid is selected from any one or more of the following: tricaprylic acid glyceride, egg yolk lecithin, soybean lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, dipalmitoyl phosphatidylcholine, distearyl phosphatidylcholine, and dioleoyl phosphatidylcholine; the negatively charged phospholipid is selected from any one or more of the following: dipalmitoyl phosphatidylglycerol, phosphatidylethanolamine, dimyristoyl phosphatidylglycerol, distearyl phosphatidylglycerol, and distearyl phosphatidic acid.

4. The preparation process of the long-acting levobupivacaine liposome injection solution according to any one of claims 1-3, characterized in that, Includes the following steps: S1: An aqueous solution of inorganic acid is used as the internal aqueous phase; the concentration of the aqueous solution of inorganic acid is 0.25 mol / L to 0.30 mol / L; S2: Levobupivacaine, neutral phospholipids, negatively charged phospholipids, cholesterol and triglycerides are dissolved in an organic solvent according to the mass ratio, and then dissolved by water bath or ultrasonic treatment to obtain the lipid phase after dissolution; S3: Add lysine and glucose to water according to the mass ratio, stir and dissolve at room temperature to obtain the external aqueous phase; S4: The internal aqueous phase in S1 is mixed with the lipid phase in S2 and homogenized and sheared to form a primary emulsion; then the external aqueous phase in S3 is divided into two parts, denoted as external aqueous phase A and external aqueous phase B respectively; the primary emulsion is first mixed with external aqueous phase A and homogenized and sheared a second time to form a secondary emulsion; then the secondary emulsion is mixed evenly with external aqueous phase B, and the organic solvent is removed by aeration to obtain crude liposomes, which are long-acting liposome intermediates; S5: Add the long-acting liposome intermediate from S4 to physiological saline, and finally concentrate it by tangential flow ultrafiltration to obtain the concentrate, which is the levobupivacaine long-acting liposome injection solution.

5. The preparation process of a long-acting levobupivacaine liposome injection solution according to claim 4, characterized in that, In step S1, the inorganic acid aqueous solution is a phosphoric acid solution with a concentration of 0.27 mol / L to 0.28 mol / L.

6. The preparation process of a long-acting levobupivacaine liposome injection solution according to claim 4, characterized in that, The organic solvent mentioned in step S2 includes any one or more of anhydrous ethanol, chloroform, dichloromethane, and methanol; the temperature during the water bath treatment is 25±1℃.

7. The preparation process of a long-acting levobupivacaine liposome injection solution according to claim 4, characterized in that, In step S3, the water is water for injection, and the mass fractions of lysine and glucose in the external aqueous phase are 0.4%-0.8% (w / w) and 3.5%-5.5% (w / w), respectively.

8. The preparation process of a long-acting levobupivacaine liposome injection solution according to claim 4, characterized in that, In S4, the volume ratio of lipid phase, inner aqueous phase, outer aqueous phase A, and outer aqueous phase B is 1:0.8~1.2:2~6:12~19; in the process of forming the primary emulsion through homogenization shearing, the homogenization shearing temperature is 20℃~25℃, the linear velocity is 6-10m / s, and the time is 10-15min; the linear velocity of the second homogenization shearing is 2-5m / s, the temperature is 20℃~25℃, and the time is 60-300s; the gas used for removing organic solvents by aeration is nitrogen.

9. The preparation process of a long-acting levobupivacaine liposome injection solution according to claim 4, characterized in that, In S5, the volume ratio of the long-acting liposome intermediate to physiological saline is 1:6-8; the ultrafiltration column used for ultrafiltration concentration is an mPES hollow fiber membrane column with a pore size of 750KD; the particle size D50 of the levobupivacaine long-acting liposome injection solution is 25-40um, and the appearance is a white suspension; the encapsulation efficiency of the levobupivacaine long-acting liposome injection solution is greater than 90%.

10. The use of the levobupivacaine long-acting liposome injection according to any one of claims 1-3 or the levobupivacaine long-acting liposome injection prepared by the method according to any one of claims 4-9 in the field of analgesic drug preparation.

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