Bupivacaine sustained-release gel injection as well as preparation method and application thereof

Abstract

The invention relates to a bupivacaine sustained-release gel injection as well as a preparation method and application thereof. The bupivacaine sustained-release gel injection comprises the following components: bupivacaine, a degradable polymer, an alkaline additive and a biocompatible organic solvent. The bupivacaine sustained-release gel injection provided by the invention has higher drug loading capacity and lower burst release level, is convenient to administrate, can release entrapped bupivacaine within 5-7 days, takes effect quickly, and can play a continuous analgesic role in vivo.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a bupivacaine sustained-release gel injection, a preparation method thereof and an application thereof. Background Art

[0002] Postoperative pain is the pain that occurs after surgery. It is a type of acute pain, mainly caused by the stimulation of the acute trauma (incision) caused by the surgery itself. The peak period is generally 24-48 hours after surgery, and the duration usually does not exceed 7 days. However, if the pain is not effectively controlled in the early stages, it may develop into chronic postoperative pain, seriously affecting the patient's quality of life.

[0003] Bupivacaine is an amide local anesthetic frequently used in clinical practice. 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 due to its long-lasting local anesthetic effect, obvious separation of sensory and motor block, and strong anesthetic effect. The first product of bupivacaine to be launched on the market was bupivacaine hydrochloride injection, which was developed and launched by Hospira in the United States in 1972 under the trade name of Marcaine. It is used for anesthesia and analgesia in surgical operations, oral operations, diagnostic and therapeutic operations, and obstetric operations. Due to its short half-life, a single injection can only maintain analgesic effect for about 5 hours. In order to meet the analgesic needs, clinically, catheter implantation, self-controlled analgesic pumps, and nerve destruction are usually used to maintain the therapeutic effect. This not only brings unnecessary pain and physical and mental harm to patients, but also wastes medical resources and increases medical expenses. Therefore, the development of long-acting preparations of bupivacaine can not only reduce the number of injections, lower treatment costs, and alleviate the economic burden on patients, but also reduce the consumption of medical resources and transportation costs, and has huge social and economic benefits.

[0004] Bupivacaine liposome injection (trade name EXPAREL) developed by Pacira Pharmaceuticals in the United States is the first liposome local anesthetic approved for clinical use. It is a multivesicular liposome with a honeycomb structure produced based on DepoFoam technology. A single dose of direct injection can produce analgesia for up to 72 hours. Exparel was first approved in 2011 for local infiltration anesthesia, and was further approved in 2018 for brachial plexus block with interscalene access. It has shown multiple advantages over bupivacaine hydrochloride injection in many clinical trials such as breast augmentation surgery, total knee replacement surgery, and inguinal hernia repair surgery. However, Exparel has the defects of easy rupture of vesicles, limited embedding rate and drug loading, and poor stability. Durect in the United States has developed a bupivacaine gel solution (trade name Posimir). The core of this technology is that sucrose acetate isobutyrate (SAIB), benzyl alcohol and bupivacaine are mixed into a liquid and then injected to form a drug reservoir for sustained release. It is currently only suitable for intra-articular administration, and clinical data show that its sustained release can only last for 24 hours.

[0005] Therefore, it is necessary to develop a longer-acting sustained-release preparation and a preparation method for injectable use to solve the above problems. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a bupivacaine sustained-release gel injection and a preparation method and application thereof. The bupivacaine sustained-release gel injection provided by the present invention has a high drug loading and a low burst release level, is easy to administer, can extend the release of the encapsulated bupivacaine to 5-7 days, has a rapid onset of action, and can exert a sustained analgesic effect.

[0007] To achieve this object, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present invention provides a bupivacaine sustained-release gel injection, the components of which include bupivacaine, a degradable polymer, an alkaline adjuvant and a biocompatible organic solvent.

[0009] When an organic solvent is used as a diluent for a biodegradable polymer to prepare a gel reservoir, there is usually a problem of excessive burst release due to the diffusion of the initial organic solvent. The present invention unexpectedly found that the addition of an alkaline auxiliary agent can effectively control the burst release of bupivacaine. The reason for this may be that the alkaline auxiliary agent interacts with the acidic groups of the polymer, increasing the viscosity, thereby slowing down the degradation of the polymer and delaying the burst release.

[0010] In addition, alkaline adjuvants dissolve together with the drug in the body, which can effectively improve the acidic environment caused by the degradation of biopolymers, thereby reducing the protonation of bupivacaine in the acidic environment, and to a certain extent avoid the obstacle of protonated bupivacaine being unable to enter nerve cells after ionization, thereby effectively prolonging the analgesic effect of bupivacaine.

[0011] Preferably, the components of the bupivacaine sustained-release gel injection include, by weight, 1 part of bupivacaine, 0.2-10 parts of a degradable polymer, 0.01-2 parts of an alkaline auxiliary agent, and 0.5-300 parts of a biocompatible organic solvent.

[0012] Preferably, the components of the bupivacaine sustained-release gel injection include, by weight, 1 part of bupivacaine, 0.5-6 parts of a degradable polymer, 0.04-0.3 parts of an alkaline auxiliary agent, and 1-20 parts of a biocompatible organic solvent.

[0013] In the present invention, the degradable polymer can be, for example, 0.5 parts, 1 parts, 2 parts, 4 parts, 6 parts, etc.; the alkaline auxiliary agent can be, for example, 0.04 parts, 0.08 parts, 0.12 parts, 0.24 parts, 0.3 parts, etc.; the biocompatible organic solvent can be, for example, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, etc.

[0014] Preferably, the degradable polymer includes any one of polylactic acid-polyethylene glycol copolymer (PELA), lactide-glycolide copolymer (PLGA) or polylactide (PLA) or a combination of at least two thereof.

[0015] Preferably, the percentage of polyethylene glycol in the polylactic acid-polyethylene glycol copolymer is 2-40% (for example, 2%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, etc.), preferably 5-30%.

[0016] Preferably, in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50-85:15 (for example, it may be 50:50, 60:40, 70:30, 80:20, 85:15, etc.), preferably 75:25-85:15.

[0017] Preferably, the molecular weight of the degradable polymer is 5-30 kDa (eg, 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, etc.), preferably 10-25 kDa.

[0018] Preferably, the biocompatible organic solvent includes any one of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetone, 2-pyrrolidone, propylene carbonate, triacetin, benzyl benzoate or propylene glycol, or a combination of at least two thereof, preferably N-methylpyrrolidone.

[0019] Preferably, the alkaline auxiliary agent includes any one of arginine, lysine, magnesium hydroxide, calcium hydroxide, calcium carbonate, magnesium carbonate, aluminum hydroxide, sodium bicarbonate or a magnesium-aluminum mixture, or a combination of at least two thereof.

[0020] Preferably, the alkaline auxiliary agent includes any one of arginine (ARG) or lysine (LYS) or a combination of both.

[0021] In a second aspect, the present invention provides a method for preparing the bupivacaine sustained-release gel injection according to the first aspect, the preparation method comprising the following steps:

[0022] (1) mixing a degradable polymer, a biocompatible organic solvent and an alkaline auxiliary agent to obtain a sustained-release solution;

[0023] (2) Adding bupivacaine to the sustained-release solution and stirring to dissolve the solution to obtain the bupivacaine sustained-release gel injection.

[0024] In a third aspect, the present invention provides a use of the bupivacaine sustained-release gel injection according to the first aspect in the preparation of analgesic or local anesthetic products.

[0025] Compared with the prior art, the present invention has at least the following beneficial effects:

[0026] (1) The present invention uses a degradable polymer as a sustained-release material and is combined with an alkaline auxiliary agent to effectively control the burst release of the drug in the bupivacaine sustained-release gel injection, prolong the duration of action, reduce the number of dosing times and toxic side effects, and has a rapid onset in the body and excellent analgesic effect.

[0027] (2) The preparation method provided by the present invention has a simple process, no drug loss during the preparation process, high drug loading capacity, and is conducive to large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is the bupivacaine sustained-release gel injection liquid in Example 1.

[0029] Figure 2 The bupivacaine sustained-release gel injection in Example 1 was injected with pH 7.4 phosphate buffer to form an in situ gel.

[0030] Figure 3 This is the rheological curve of bupivacaine at 25°C in Example 1.

[0031] Figure 4 This is the effect-time diagram of the bupivacaine sustained-release gel injection in Example 1 after administration to guinea pigs.

[0032] Figure 5 The cumulative pain score-time curve of bupivacaine sustained-release gel injection in rats in Examples 1, 2, and 3.

[0033] Figure 6 Graph showing mechanical pain threshold of rats for bupivacaine gel injection in Examples 1, 2, and 3. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below in conjunction with the accompanying drawings and through specific implementation methods. However, the following examples are only simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention shall be subject to the claims.

[0035] Examples 1-10, Comparative Examples 1-2

[0036] Examples 1-10 and Comparative Example 1 respectively provide a bupivacaine sustained-release gel injection, and Comparative Example 2 provides a bupivacaine sustained-release microsphere, the components of which are as follows:

[0037]

[0038]

[0039] The only difference between Example 4 and Example 3 is that the molecular weight of the polymer PLA is 29 kDa;

[0040] The only difference between Example 5 and Example 3 is that the polymer is 11 kDa PLGA50:50;

[0041] The only difference between Example 6 and Example 1 is that the amount of organic solvent NMP is reduced to 1.2 g;

[0042] The only difference between Example 7 and Example 2 is that the organic solvent is 7 g DMSO;

[0043] The only difference between Example 8 and Example 2 is that the organic solvent is 6 g of NMP and 2 g of DMSO;

[0044] The only difference between Example 9 and Example 2 is that the organic solvent is 2 g of NMP and 6 g of DMSO;

[0045] The only difference between Example 10 and Example 3 is that the amount of organic solvent NMP is increased to 100 g;

[0046] The only difference between Comparative Example 1 and Example 1 is that no alkaline auxiliary agent is added.

[0047] The preparation method of the bupivacaine sustained-release gel injection provided in Examples 1-10 and Comparative Example 1 comprises the following steps:

[0048] (1) mixing a degradable polymer, a biocompatible organic solvent and an alkaline auxiliary agent to obtain a sustained-release solution;

[0049] (2) Adding bupivacaine in small amounts and multiple times to the sustained-release solution under stirring, stirring and dissolving, thereby obtaining the bupivacaine sustained-release gel injection.

[0050] The preparation method of bupivacaine sustained-release microspheres provided in Comparative Example 2 is an oil-in-water emulsion method, comprising the following steps: dissolving bupivacaine and a degradable polymer in an organic solvent to obtain an oil phase, using a 0.5wt% polyvinyl alcohol solution as the external aqueous phase, and homogenizing and emulsifying the formed oil-in-water emulsion, and further solidifying it into microspheres by stirring at 600rpm. The solidified microspheres are repeatedly washed with pure water for multiple times to remove residual polyvinyl alcohol, and then freeze-dried to obtain bupivacaine microspheres.

[0051] Test Example 1

[0052] Appearance, viscosity, in vitro release testing

[0053] Test method: The viscosity of bupivacaine sustained-release gel injection was tested using a cone-plate rheometer, and the bupivacaine sustained-release gel injection was injected into a pH 7.4 phosphate buffer in vitro to test the in vitro release efficiency.

[0054] like Figure 1 As shown, the bupivacaine sustained-release gel injection prepared in Example 1 has a light yellow transparent liquid appearance and good fluidity.

[0055] like Figure 2 As shown, the bupivacaine sustained-release gel injection prepared in Example 1 was injected into a pH 7.4 phosphate buffer to form a gel-like semisolid.

[0056] like Figure 3 As shown, the shear stress of the bupivacaine sustained-release gel injection prepared in Example 1 is proportional to the shear rate, and the viscosity is independent of the shear rate, which is close to a Newtonian fluid.

[0057] The products provided in Examples 1-10 and Comparative Examples 1-2 were subjected to viscosity and in vitro release tests, and the results are shown in Table 1.

[0058] Table 1

[0059]

[0060] The test results show that the bupivacaine sustained-release gel injection in Examples 1-3 can achieve slow release of the drug within 7 days after being injected into a pH 7.4 phosphate buffer in vitro, effectively prolonging the drug's duration of action.

[0061] The molecular weight of the polymer used in Example 4 is too high, resulting in slow drug release, and the cumulative release in 7 days is only 71%; in Example 5, PLGA50:50 with a polymer of 11 kDa is used, and the cumulative release in 1 day of the obtained injection liquid exceeds 80%, and the release rate is too fast; in Example 6, the amount of organic solvent used is too low, the raw material drug cannot be completely dissolved, and it is dispersed in granules. After heating and stirring, the particles gradually dissolve, and the problem of needle blocking occurs during the release test. Therefore, it is judged that the drug combination is not suitable for the preparation of bupivacaine gel injection; in Examples 7-9, DMSO or a mixed solvent of NMP and DMSO is used, and the cumulative release in vitro in 7 days is 71-80%, and the release rate is slow; in Example 10, the amount of organic solvent used is too high, and the overall in vitro release is too fast, and the sustained release effect cannot be achieved.

[0062] In comparative example 1, no alkaline auxiliary agent was added, and the obtained injection liquid released too fast in 4-7 days in in vitro testing, with the cumulative release in 4 days reaching 87%, and the sustained release effect could not be achieved; the in vitro release of the microspheres provided in comparative example 2 was overall slow, and could not meet the requirement of sufficient release in 7 days.

[0063] Test Example 2

[0064] Anesthetic effect test

[0065] Test samples: bupivacaine gel injection prepared in Example 1 and commercially available bupivacaine hydrochloride injection

[0066] Test Method: The local anesthetic effect of the samples on guinea pigs was tested using the needle prick method.

[0067] Male adult guinea pigs weighing 350-450g were selected and purchased from Guangdong Weitong Lihua Experimental Animal Technology Co., Ltd. The experimental animals were raised in the animal room of the Experimental Animal Center of Hunan University of Traditional Chinese Medicine. After the animals were purchased and adapted for 5 days and passed the veterinary inspection, they were shaved (or depilated) with the midline of the guinea pig's back as the center line, and the shaved (or depilated) area was not less than 6cm*6cm. After continuing to be raised for 12 hours, they were placed on a mouse board and acupunctured on the skin of the shaved area for a total of 8 stimulations. Animals with negative reactions (no contraction reaction in the skin area of ​​the guinea pig's back after acupuncture or guinea pig screaming) were eliminated, and qualified guinea pigs were screened for unified breeding.

[0068] Take 10 guinea pigs that have passed the screening and are randomly divided into 2 groups, 5 in each group, and the grouping and dosage are as follows: control group (bupivacaine hydrochloride injection, 10 mg / kg), Example 1 group (10 mg / kg). During the experiment, a needle is used to stimulate the skin of the administration site. If there is a contraction reaction or guinea pig screaming in the skin area at the stimulation site, it is considered as a positive reaction, otherwise it is a negative reaction. The average number of negative times at a single time point is calculated for each group to obtain the average number of negative times at the time point of each group, and the average painless reaction rate (effect) is obtained from the average number of negative times.

[0069] Test results: Effects of bupivacaine sustained-release gel injection in guinea pigs after administration - time Figure 4 As shown, the control group had almost no analgesic effect after 6 hours of administration, and the average analgesic reaction rate of Example 1 remained above 50% after 7 days of administration, indicating that the bupivacaine gel injection provided by the present invention has a long-lasting efficacy.

[0070] Test Example 3

[0071] Analgesic effect test

[0072] Test samples: Bupivacaine gel injection in Examples 1-3, commercially available bupivacaine hydrochloride injection Test method:

[0073] SD rats (SPF grade), adult males weighing 250-300 g and aged 8-10 weeks, were purchased from Beijing Huafukang Biotechnology Co., Ltd. The rats were weighed after 4 days of adaptation and divided into plantar incision group and non-plantar incision group according to their body weight. The plantar incision group was divided into 5 groups according to body weight, with 6 rats in each group. The non-plantar incision group was tested for heat pain threshold and was divided into 5 groups according to body weight and heat pain threshold, with 6 rats in each group.

[0074] The rats were fasted for 12 hours before administration. When the rats were administered, they were anesthetized with isoflurane and 30,000 units of penicillin potassium were injected into the triceps surae. The rats were fixed in a prone position on a rat fixing frame, and a perforated towel was laid to expose the right lower limbs of the rats and shave the hair. The rats were disinfected with iodine and alcohol three times, and a longitudinal incision of about 6-8 mm long was made in the middle of the right thigh to expose the subcutaneous muscles. After blunt separation of the biceps femoris, semitendinosus, and semimembranosus with hemostatic forceps, a white, thick sciatic nerve was visible. A needle was inserted into the muscle about 1.5 mm next to the sciatic nerve, 1 / 3 of the needle was injected, 0.5 mL of the drug was injected, the muscles were trimmed, and the wound was sutured.

[0075] The rats in the non-plantar incision group were not modeled. The modeling method of the rats in the plantar incision group was as follows: after the sciatic nerve injection, the rat's right foot was taken as the starting point at a position about 0.5 cm away from the heel, and an incision was made in the middle of the sole toward the toe. The incision was about 1 cm long. The plantar muscle was lifted with forceps and cut longitudinally by 0.8-1 cm. It was completely incised and separated to both sides, keeping the origin and attachment of the muscle intact. After pressing to stop bleeding, the incision was closed with 5-0 sutures in an interrupted mattress suture method.

[0076] The analgesic efficacy and duration of the test samples were evaluated by cumulative pain scores, mechanical pain tests, and thermal pain tests:

[0077] 1) Cumulative pain score detection method: Rats were placed on a metal net, each in a separate small compartment, and adapted for 2 minutes; then observed for 3 minutes, with the most commonly used posture within 1 minute as the standard, and observed for a total of 3 minutes. The data were recorded 3 times and the cumulative sum was the cumulative pain score. The scoring standard referred to the Brennan method.

[0078] 2) Mechanical pain detection method: The rats were placed on a metal net, each in a separate small compartment. After 2 min of adaptation, when the animals were in a quiet and awake state, an electronic analgesic was used to stimulate the skin within 2 mm of the toe end of the plantar incision of the right hind paw. Each test was performed 3 times with an interval of 5-10 s. The values ​​were recorded and the average was taken as the mechanical pain threshold.

[0079] 3) Thermal pain test method: Turn on the hot plate instrument and set the initial temperature to 52±0.5℃. Once the temperature is reached, the experiment can be carried out. Remove the organic cover on the hot plate, place the rat on the hot plate, close the organic cover, click the test, and lock the time and record it after the rat licks its right foot for the first time. Take the average of the three threshold values ​​as the thermal pain threshold of the rat. If the rat does not respond for 60 seconds during the test, its foot should be immediately removed from the hot plate to avoid burns, and its threshold is calculated as 60 seconds.

[0080] The groups and dosages were as follows: blank group (vehicle group, NMP+PELA, no drug gel), positive control group (bupivacaine hydrochloride injection, 2.5 mg / mouse), Example 1 group (10 mg / mouse), Example 2 group (10 mg / mouse), Example 3 group (10 mg / mouse).

[0081] Test results:

[0082] The cumulative pain test results of the blank group, the positive control group, and the Example 1-3 groups are shown in Table 2. For example, the cumulative pain score-time change curve of the bupivacaine sustained-release gel injection in the Example 1-3 groups is as follows: Figure 5 shown.

[0083] Table 2

[0084]

[0085]

[0086] The results showed that the cumulative pain scores of the blank group rats showed a downward trend over time, and the scores of the positive control group rats were much lower than those of the blank group (vehicle group) at 0.5h after administration, and showed an upward trend, and a downward trend after 2h, and were close to the blank group (vehicle group) at 24h, 48h, 72h, 96h, 120h, and 168h. The scores of the rats in Example 1, Example 2, and Example 3 groups were much lower than those of the blank group at 0.5h after administration, and showed a downward trend, and were still lower than the blank group at 168h. The cumulative pain scores of Example 1 and Example 2 were close, and the cumulative pain score of Example 3 was slightly higher than that of Example 1 and Example 2.

[0087] The mechanical pain test results of the blank group (solvent group), the positive control group, and the Example 1-3 groups are shown in Table 3. For example, the mechanical pain threshold values ​​of rats with bupivacaine gel injection in Examples 1, 2, and 3 are shown in Table 3. Figure 6 shown.

[0088] Table 3

[0089]

[0090] The results showed that the mechanical pain threshold of rats in the positive control group at 0.5-2h was significantly higher than that in the blank group, and the mechanical pain threshold at 24-168h was close to that in the blank group. The mechanical pain thresholds of the Example 1 group, the Example 2 group, and the Example 3 group at 0.5-168h after administration were all higher than those in the positive control group and the blank group.

[0091] The thermal pain test results of the blank group, positive control group, and Example 1-3 groups are shown in Table 4.

[0092] Table 4

[0093]

[0094] The results showed that the thermal pain threshold of the rats in the blank injection group did not change much over time, indicating that the rats in this group did not experience sensory block; the duration of sensory block in the rats in the positive control group was about 2 hours, and did not exceed 24 hours. The rats in Example 1 and Example 2 groups showed long-term sensory block compared with the blank group and the positive control group. The rats in Example 3 group showed sensory block 0.5-120 hours after administration compared with the blank group and the positive control group, and the value at 168 hours was close to that of the blank group.

[0095] The comprehensive results show that the bupivacaine gel injection prepared by the present invention has obvious sustained-release and long-acting analgesic effects.

Claims

1. A bupivacaine sustained-release gel injection, characterized in that: The components of the bupivacaine sustained-release gel injection include bupivacaine, a degradable polymer, an alkaline auxiliary agent and a biocompatible organic solvent.

2. The bupivacaine sustained-release gel injection according to claim 1, characterized in that: The components of the bupivacaine sustained-release gel injection include, by weight, 1 part of bupivacaine, 0.2-10 parts of a degradable polymer, 0.01-2 parts of an alkaline auxiliary agent, and 0.5-300 parts of a biocompatible organic solvent; Preferably, the components of the bupivacaine sustained-release gel injection include, by weight, 1 part of bupivacaine, 0.5-6 parts of a degradable polymer, 0.04-0.3 parts of an alkaline auxiliary agent, and 1-20 parts of a biocompatible organic solvent.

3. The bupivacaine sustained-release gel injection according to claim 1 or 2, characterized in that: The degradable polymer includes any one of polylactic acid-polyethylene glycol copolymer, lactide-glycolide copolymer or polylactide or a combination of at least two thereof.

4. The bupivacaine sustained-release gel injection according to claim 3, characterized in that: In the polylactic acid-polyethylene glycol copolymer, the percentage of polyethylene glycol is 2-40%, preferably 5-30%; Preferably, in the lactide-glycolide copolymer, the molar ratio of lactide to glycolide is 50:50-85:15, preferably 75:25-85:

15.

5. The bupivacaine sustained-release gel injection according to any one of claims 1 to 4, characterized in that: The molecular weight of the degradable polymer is 5-30 kDa, preferably 10-25 kDa.

6. The bupivacaine sustained-release gel injection according to any one of claims 1 to 5, characterized in that: The biocompatible organic solvent includes any one of N-methylpyrrolidone, dimethyl sulfoxide, acetone, 2-pyrrolidone, propylene carbonate, triacetin, benzyl benzoate or propylene glycol, or a combination of at least two thereof.

7. The bupivacaine sustained-release gel injection according to any one of claims 1 to 6, characterized in that: The alkaline auxiliary agent includes any one of arginine, lysine, magnesium hydroxide, calcium hydroxide, calcium carbonate, magnesium carbonate, aluminum hydroxide, sodium bicarbonate or a magnesium-aluminum mixture, or a combination of at least two thereof.

8. The bupivacaine sustained-release gel injection according to claim 7, characterized in that: The alkaline auxiliary agent includes any one of arginine and lysine or a combination of the two.

9. A method for preparing the bupivacaine sustained-release gel injection according to any one of claims 1 to 8, the method comprising the following steps: (1) mixing a degradable polymer, a biocompatible organic solvent and an alkaline auxiliary agent to obtain a sustained-release solution; (2) Adding bupivacaine to the sustained-release solution and stirring to dissolve the solution to obtain the bupivacaine sustained-release gel injection.

10. Use of the bupivacaine sustained-release gel injection according to any one of claims 1 to 8 in the preparation of analgesic or local anesthetic products.

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