A low irritation, high safety benzoyl aconine temperature-sensitive analgesic gel injection and a preparation method and application thereof

Abstract

The application discloses a low-stimulus and high-safety benzoyl aconine original base temperature-sensitive analgesic gel injection as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The injection takes benzoyl aconine original base as a core analgesic component, constructs a triple heart protection system of'sub-anesthetic dose lidocaine + ammonium glycyrrhizinate + magnesium sulfate', cooperates with a poloxamer 407 temperature-sensitive gel matrix, and is supplemented with a cosolvent and an antioxidant, has a pH value of 5.5-6.5, can be injected at room temperature, and is quickly gelled at body temperature to realize long-acting controlled release. The preparation has high analgesic intensity, no addiction, slight injection pain, controllable cardiotoxicity, and can maintain analgesia for more than 12 hours after single administration, is suitable for local targeted treatment of moderate and severe chronic pain, neuropathic pain and the like, and has significant clinical advantages and popularization value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a compound thermosensitive gel analgesic preparation of traditional Chinese medicine monomers for local injection, and more particularly to a benzoyl aconitine thermosensitive analgesic gel injection with a triple cardiac protection mechanism, non-addictive, and mild injection pain, as well as the preparation method of the preparation and its application in the treatment of chronic pain. Background Technology

[0002] Pain is one of the most common clinical symptoms, especially moderate to severe chronic pain, neuropathic pain, and neck, shoulder, back, and leg pain caused by cold and dampness obstruction, which seriously affects patients' quality of life. Currently, clinical analgesics are mainly divided into three categories: opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), and traditional Chinese medicine analgesics. However, all have significant technical limitations: ① Opioid analgesics: While possessing high analgesic potency, they act on central opioid receptors, easily leading to addiction, dependence, and tolerance. They also have potentially fatal side effects such as respiratory depression, severe constipation, and drowsiness. As strictly controlled drugs, their clinical use is limited, failing to meet the long-term medication needs of patients with chronic pain. ② NSAIDs: Represented by ibuprofen, diclofenac sodium, and celecoxib, these are commonly used mild to moderate analgesics. However, these drugs are only effective for inflammation-related pain, with limited analgesic effects on moderate to severe chronic pain and neuropathic pain. Furthermore, long-term oral administration can easily cause adverse reactions such as gastrointestinal ulcers, bleeding, liver and kidney damage, and cardiovascular risks, failing to meet the clinical need for long-term, safe, and potent analgesia. Meanwhile, nonsteroidal anti-inflammatory drugs lack long-acting formulations for local targeted delivery, resulting in high systemic exposure and poor safety and compliance; ③ No injection solution available in summer: As a commonly used Chinese medicine analgesic injection, although it is not addictive, it has a core defect—the alkaloids are highly irritating when injected intramuscularly, causing obvious stinging, burning and distending pain, resulting in poor patient compliance. Furthermore, it is a common aqueous solution formulation, which has a rapid onset of action but a short duration of action, requiring frequent administration. It lacks a clear cardioprotective mechanism, and its safety needs to be improved. ④ Aconite-based traditional Chinese medicine preparations: Monoester aconite alkaloids such as benzoyl aconitine have significant analgesic effects, with analgesic intensity superior to that of summer pine, and have specific efficacy for neuropathic pain. However, aconite components have a narrow safety window and are prone to causing arrhythmias by blocking the myocardial Nav1.5 sodium channel, resulting in a high risk of cardiotoxicity and limiting their clinical application. Existing local analgesic preparations: Some technologies use thermosensitive gels as drug carriers, but they mostly focus on the anesthetic use of local anesthetics such as lidocaine, without combining subanesthetic doses of lidocaine with aconite alkaloids, and without constructing a triple cardioprotective system of "channel blockade + membrane stabilization + electrophysiological regulation". At the same time, existing thermosensitive gel preparations have not been optimized for the injection irritation of traditional Chinese medicine alkaloids, and cannot simultaneously achieve strong analgesia, high safety, and low injection pain. Furthermore, while a simple combination of "summer-free injection + low-dose lidocaine" is used clinically to alleviate injection pain, this combination only uses lidocaine as a local anesthetic, without addressing the toxicity control of aconitine alkaloids, and is a common aqueous injection formulation without long-lasting controlled-release effects. This is fundamentally different from the technical solution, pharmacological mechanism, and clinical application of this invention. Therefore, developing a local injectable analgesic with high analgesic potency, non-addictive properties, controllable cardiotoxicity, mild injection pain, and long-lasting sustained release is crucial to addressing unmet clinical needs and is the core research and development objective of this invention. Summary of the Invention

[0003] This invention aims to overcome the shortcomings of existing analgesic preparations and solve the following core problems in the prior art: 1. Benzoyl aconitine has excellent analgesic effect but high cardiotoxicity risk, limiting its clinical application; 2. Existing traditional Chinese medicine analgesic injections are highly irritating, causing significant pain and poor patient compliance; 3. Ordinary aqueous injections have a short duration of action and require frequent administration, failing to meet the needs of long-term chronic pain control; 4. Opioids are highly addictive and have significant side effects, and nonsteroidal anti-inflammatory drugs (NSAIDs) have many adverse reactions with long-term use, making them unsafe for long-term treatment of chronic pain.

[0004] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: (I) The local injection benzoyl aconitine thermosensitive analgesic gel provided by the present invention adopts a core formulation of "analgesic active ingredient + cardioprotective system + thermosensitive gel matrix + solubilizing and antioxidant excipients", which takes into account efficacy, safety and dosage form characteristics. The specific technical solution is as follows: (1) The core formulation consists of the following per 1 mL of the injection: benzoyl aconitine 0.18-0.22 mg, lidocaine 0.45-0.55 mg, glycyrrhizic acid monoammonium salt 0.9-1.1 mg, magnesium sulfate 1.35-1.65 mg, poloxamer 407 180-220 mg, propylene glycol 0.045-0.055 mL, vitamin C 0.18-0.22 mg, with the remainder being water for injection.

[0005] As a preferred formulation, each 1 mL contains: benzoyl aconitine 0.19–0.21 mg, lidocaine 0.48–0.52 mg, glycyrrhizic acid monoammonium salt 0.95–1.05 mg, magnesium sulfate 1.42–1.58 mg, poloxamer 407 190–210 mg, propylene glycol 0.048–0.052 mL, vitamin C 0.19–0.21 mg, with the remainder being water for injection.

[0006] In one specific embodiment, each 1 mL contains: 0.2 mg benzoyl aconitine, 0.5 mg lidocaine, 1.0 mg glycyrrhizic acid monoammonium salt, 1.5 mg magnesium sulfate, 200 mg poloxamer 407, 0.05 mL propylene glycol, 0.2 mg vitamin C, and the balance being water for injection.

[0007] Accordingly, the present invention also provides a 2mL injection solution, each 2mL containing: benzoyl aconitine 0.36-0.44 mg, lidocaine 0.9-1.1 mg, glycyrrhizic acid monoammonium salt 1.8-2.2 mg, magnesium sulfate 2.7-3.3 mg, poloxamer 407 360-440 mg, propylene glycol 0.09-0.11 mL, vitamin C 0.36-0.44 mg, and the balance being water for injection.

[0008] As a preferred formulation, each 2 mL contains: benzoyl aconitine 0.38–0.42 mg, lidocaine 0.95–1.05 mg, glycyrrhizic acid monoammonium salt 1.9–2.1 mg, magnesium sulfate 2.85–3.15 mg, poloxamer 407 380–420 mg, propylene glycol 0.095–0.105 mL, vitamin C 0.38–0.42 mg, with the remainder being water for injection.

[0009] In one specific embodiment, each 2 mL contains: benzoyl aconitine 0.4 mg, lidocaine 1.0 mg, glycyrrhizic acid monoammonium salt 2.0 mg, magnesium sulfate 3.0 mg, poloxamer 407 400 mg, propylene glycol 0.1 mL, vitamin C 0.4 mg, and the balance being water for injection; the injection solution is used for local injection to treat moderate to severe chronic pain. The core components and concentration ranges of the prescription are as follows: Table 1: Optimal Dosage Table for 2mL Analgesic Injection (Suitable for Direct Clinical Trials / Production) Components Component categories 2ml optimal dose Measurement accuracy control core role Benzoyl aconitine Core analgesic ingredients 0.4mg ±0.02mg To exert the main analgesic effect, the dosage is precise and controllable. Lidocaine Cardiac protection system 1.0 mg ±0.05 mg It occupies 15 sodium ion channels in the heart, blocking the toxic pathway of benzoyl aconitine to the heart and reducing the risk of cardiotoxicity. Glycyrrhizic acid monoammonium salt Cardiac protection system 2.0 mg ±0.1 mg Enhances the protective effect on cardiomyocytes Magnesium sulfate Cardiac protection system 3.0 mg ±0.15 mg Regulate myocardial ion balance and reduce the risk of arrhythmia Polosham 407 Thermosensitive gel matrix 400 mg ±20 mg Ensures that a gel forms locally after injection to prolong the drug's effect. Propylene glycol Cosolvent 0.1 mL ±0.005 mL Improve the solubility of poorly soluble components and ensure formulation stability Vitamin C antioxidants 0.4 mg ±0.02 mg Prevents oxidation of active ingredients and extends shelf life Water for Injection solvent Add to 2.0 mL Accurate to 2.0 mL As a matrix, it ensures the sterility and impurity-free nature of the formulation.

[0010] (2) Key characteristics of the formulation ① pH value: Adjusted to 5.5-6.5, preferably 6.0, close to the pH value of human tissue, with no obvious tissue irritation; ② Temperature-sensitive properties: At 20℃-28℃ (room temperature), it is a clear, low-viscosity flowing liquid that can be easily injected through a 25G-27G syringe; at 35℃-39℃ (human body temperature), it forms a semi-solid gel within 1-5 minutes, creating a drug reservoir locally; ③ Content uniformity: Benzoyl aconitine content uniformity ≤±3%, preferably ≤±2%; lidocaine content uniformity ≤±2%; ④ Stability: Under light-protected refrigeration conditions at 2℃-8℃, the degradation rate of benzoyl aconitine is ≤5% within the shelf life, and the temperature-sensitive properties show no significant change.

[0011] The lidocaine of this invention at a subanesthetic dose (0.45–0.55 mg lidocaine per milliliter of injection solution) has the core pharmacological use of competitively blocking the myocardial Nav1.5 sodium channel. Combined with the cell membrane stabilizing effect of glycyrrhizic acid monoammonium salt and the electrophysiological regulatory effect of magnesium sulfate, it constructs a triple cardioprotective system specifically for reducing the cardiotoxicity of benzoyl aconitine, unlike the conventional use of lidocaine in existing technologies, which is only for reducing injection pain. Furthermore, the mass ratio of glycyrrhizic acid monoammonium salt to benzoyl aconitine in this invention is (4–6):1; the mass ratio of magnesium sulfate to benzoyl aconitine is (6–8):1. This ratio range represents the optimal range for efficacy and safety.

[0012] (II) Preparation method This invention provides a method for preparing the above-mentioned benzoyl aconitine thermosensitive analgesic gel injection, strictly controlling key process parameters to ensure formulation stability and efficacy consistency. The specific steps are as follows: ① Gel matrix dissolution: Under low temperature conditions of 0℃~10℃, the prescribed amount of poloxamer 407 is added to an appropriate amount of water for injection, and stirred at a rate of 200~500r / min for 2~6 hours until completely dissolved, forming a clear gel matrix solution; ② Excipient addition: The prescribed amount of solubilizer and antioxidant are added to the gel matrix solution, and stirring is continued at low temperature for 10~20 minutes to mix well; ③ Addition of cardioprotective ingredients: Add the prescribed amount of lidocaine, glycyrrhizic acid monoammonium salt, and magnesium sulfate in sequence, and stir at low temperature until completely dissolved to form a mixed solution; ④ Addition of active ingredients: Add the prescribed amount of benzoyl aconitine to the above mixed solution, and stir thoroughly at low temperature for 15-30 minutes until evenly dissolved; ⑤ pH adjustment and volume adjustment: Adjust the pH of the mixed solution to 5.5-6.5 (preferably 6.0) with 0.1mol / L hydrochloric acid or sodium hydroxide solution, add water for injection to the total volume of the unit preparation, and stir well; ⑥ Sterilization and filling: Sterilize the above solution by filtering it through a 0.22μm microporous membrane, and fill it into sterile injection vials under Class 100 cleanroom conditions to obtain the finished product; ⑦ Storage: Store the finished product at 2℃-8℃ protected from light.

[0013] (III) Clinical Application The formulation of this invention is for local targeted drug delivery only, excluding intravenous and intramuscular injection routes. Specific application scenarios are as follows: ① Indications: For the treatment of moderate to severe chronic pain, neuropathic pain, cold-dampness obstruction type neck, shoulder, back and leg pain, joint pain, and soft tissue injury pain; especially suitable for patients who do not respond well to opioids or cannot tolerate the side effects of opioids; ② Administration method: One or more of local pain point injection, acupoint injection, periarticular injection, and fascial layer injection; ③ Dosage and administration: The single dose is 0.5mL to 2mL, administered 1 to 2 times daily, with the dosage adjusted according to the patient's pain level and the administration site.

[0014] The technical solution of this invention has prominent substantive features and significant progress, and has the following core beneficial effects compared with the prior art: 1. Innovative Pharmacological Mechanism, Addressing the Core Pain Point of Benzoylaconitine Cardiotoxicity: For the first time, the core application of sub-anesthetic dose lidocaine is defined as "competitive blocking of the myocardial NaV1.5 sodium channel." Combined with the cell membrane stabilizing effect of glycyrrhizic acid monoammonium salt and the electrophysiological regulatory effect of magnesium sulfate, a triple cardioprotective system is constructed. This fundamentally reduces the cardiotoxicity risk of benzoylaconitine from a pharmacological perspective, breaking through the core limitation of the clinical application of aconitine alkaloids. 2. Innovative Formulation System, Achieving Synergistic Effect of Powerful Analgesia and High Safety: A unique compound system of "benzoylaconitine + sub-anesthetic dose lidocaine + glycyrrhizic acid monoammonium salt + magnesium sulfate" is formed. Through precise proportioning, synergistic effects are achieved, ensuring both the powerful analgesic effect of benzoylaconitine (significantly superior analgesic intensity compared to Xia Tian Wu injection) and precise control of cardiotoxicity. Furthermore, it is non-addictive and has no central nervous system side effects, filling the gap in clinically available non-regulated potent analgesics. 3. Innovative Dosage Form and Efficacy: Achieving Long-Lasting Controlled Release and Low-Irritation Administration: Utilizing 18%–22% poloxamer 407 thermosensitive gel as a carrier, it achieves rapid gelation at body temperature after local injection, forming a local drug reservoir. The analgesic effect lasts for more than 10 hours, overcoming the shortcomings of traditional aqueous injections, such as short duration of action and the need for frequent administration. Simultaneously, the pH value is optimized to 5.5–6.5, combined with a subanesthetic dose of lidocaine, reducing injection pain to mild or less, manifesting only as a transient soreness. This completely solves the clinical pain point of severe injection pain in traditional Chinese medicine alkaloid injections, significantly improving patient compliance. 4. Clear Clinical Positioning and Wide Application Scenarios: Clearly defined as a "non-addictive, non-regulated, long-acting local analgesic," it avoids the addictiveness and serious side effects of opioids while compensating for the insufficient efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) for moderate to severe chronic pain. It is suitable for long-term use in patients with chronic pain and can be widely applied in multiple clinical departments such as pain management, orthopedics, rehabilitation, and traditional Chinese medicine. 5. The preparation process is stable and controllable, suitable for industrial production: The entire process employs a low-temperature dissolution process to avoid degradation of benzoyl aconitine, ensuring the uniformity and stability of the formulation content; the process steps are simple, parameters are controllable, and no special equipment is required. The injection solution of this invention not only achieves local analgesia through reasonable dosage formulation, but also ensures consistency in efficacy and safety between batches and vials through strict content uniformity control (benzoyl aconitine ≤ ±3%, lidocaine ≤ ±2%), making it more suitable for industrial-scale production. It can be directly scaled up for industrial production, and the finished product exhibits excellent stability under refrigeration conditions, meeting the quality control requirements for injections. Detailed Implementation

[0015] To make the technical solution, objectives, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to preferred embodiments. Those skilled in the art should understand that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention; the scope of protection of the present invention is not limited to the following embodiments.

[0016] Example 1: Preparation of 2mL Benzoyl aconitine thermosensitive analgesic gel injection 1. Prescription composition: Benzoyl aconitine 0.4mg, lidocaine 1.0mg, glycyrrhizic acid monoammonium salt 2.0mg, magnesium sulfate 3.0mg, poloxamer 407 400mg, propylene glycol 0.1mL, vitamin C 0.4mg, water for injection to 2.0mL, pH adjusted to 6.0.

[0017] 2. Preparation steps: (1) Under low temperature conditions of 4℃, 400mg of poloxamer 407 was added to 1.5mL of water for injection and stirred at a rate of 300r / min for 4 hours until completely dissolved to obtain a clear gel matrix solution. (2) Add 0.1 mL of propylene glycol and 0.4 mg of vitamin C, keep at 4 °C and stir for 15 minutes to obtain the first mixed solution; (3) Add 1.0 mg lidocaine, 2.0 mg glycyrrhizic acid monoammonium salt and 3.0 mg magnesium sulfate in sequence, and stir at 4°C until completely dissolved to obtain the second mixed solution; (4) Add 0.4 mg of benzoyl aconitine, keep at 4°C and stir for 20 minutes until dissolved and homogeneous to obtain the third mixed solution; (5) Adjust the pH of the third mixed solution to 6.0 with 0.1 mol / L hydrochloric acid, add water for injection to 2.0 mL, stir and mix well to obtain the drug solution; (6) The drug solution is filtered through a 0.22μm microporous membrane for sterilization and then filled into a 2mL sterile injection bottle in a Class 100 clean area; (7) Store in a cool, dark place at 2℃~8℃.

[0018] 3. Formulation characteristic testing: (1) Appearance: It is a clear, flowing liquid at 25°C and forms a semi-solid gel within 3 minutes at 37°C; (2) Content uniformity: Benzoyl aconitine content uniformity ±1.2%, lidocaine content uniformity ±0.8%, which meet the quality requirements for injections; (3) Stability: After refrigeration at 2℃~8℃ for 6 months, the degradation rate of benzoyl aconitine was 2.1%, the temperature-sensitive properties showed no significant change, and the related substances met the standards for injectable preparations.

[0019] Example 2: Preparation of 1mL Benzoyl aconitine thermosensitive analgesic gel injection 1. Prescription composition: Benzoyl aconitine 0.2mg, lidocaine 0.5mg, glycyrrhizic acid monoammonium salt 1.0mg, magnesium sulfate 1.5mg, poloxamer 407 200mg, propylene glycol 0.05mL, vitamin C 0.2mg, water for injection to 1.0mL, pH adjusted to 5.8.

[0020] 2. Preparation steps: Same as in Example 1, only adjust the amount of each component, fill into 1mL sterile injection bottles, and store in the dark at 2℃~8℃.

[0021] 3. Formulation characteristics test: It is a clear, flowing liquid at 25℃ and forms a semi-solid gel within 2 minutes at 37℃; the uniformity of benzoyl aconitine content is ±1.5%, which meets the quality requirements for injections.

[0022] Example 3: Comparative Analysis of Effects 1. Comparison Object - Experimental group: Benzoyl aconitine thermosensitive analgesic gel injection prepared in Example 1 of the present invention - Control group: Commercially available summer-free injection solution 2. Comparison of Injection Pain: The formulation of this invention has a pH of 6.0, which is neutral and mild, close to the pH of human tissue. It is supplemented with a sub-anesthetic dose of lidocaine to reduce local nerve stimulation. Furthermore, it is administered as a thermosensitive gel with low viscosity, resulting in only a slight, transient soreness during injection, without significant stinging, burning, or throbbing pain. The injection pain is mild or less. In contrast, the injection solution from Xia Tian Wu is a traditional Chinese medicine alkaloid solution with a slightly acidic pH, resulting in stronger tissue irritation. It easily produces significant stinging, throbbing, and burning sensations during injection, with most patients reporting significant pain and poor patient tolerance. Comparison of Analgesic Effect and Duration: This invention uses benzoyl aconitine as the core analgesic component, exhibiting specific analgesic effects on chronic pain and neuropathic pain, with significantly higher analgesic intensity than Xia Tian Wu. Combined with a thermosensitive gel local controlled-release system, the drug is slowly released at the injection site, and the analgesic effect of a single injection can last for more than 12 hours. Only 1-2 doses per day are needed, eliminating the need for frequent injections. Summer-Free Injection is a common aqueous solution, with rapid onset but also rapid metabolism. Its analgesic effect typically lasts only 3-4 hours, requiring frequent daily administration, increasing patient suffering and the workload of medical staff. Safety Comparison: This invention constructs a triple cardioprotective system using a combination of "subanesthetic dose lidocaine + glycyrrhizic acid monoammonium salt + magnesium sulfate," significantly reducing the cardiotoxicity risk of benzoyl aconitine from a mechanistic perspective. Simultaneously, it employs local targeted delivery, with the drug primarily acting at the injection site, resulting in extremely low systemic exposure, no addictive properties, no respiratory depression, and no serious gastrointestinal adverse reactions, demonstrating high overall safety. Summer-Free Injection lacks a targeted cardioprotective design and is administered via intramuscular injection, posing a potential risk of systemic adverse reactions; its safety control level is lower than that of this invention.

[0023] 3. Comparative Conclusion: This invention is significantly superior to Xia Tian Wu injection in terms of injection irritation, duration of analgesia, analgesic intensity, and safety. At the same time, it does not have the addictive properties and serious side effects of opioids, and has outstanding clinical advantages and promotional value. Adverse reactions and limitations

[0024] 1. Adverse reactions: This product has a high overall safety profile, with mild and transient adverse reactions; mild soreness, redness, and short-term induration may occasionally occur locally, which can be relieved on their own without special treatment; systemic adverse reactions are extremely rare, and mild dizziness, nausea, or rash may occasionally occur in sensitive individuals, which recover quickly after discontinuation of the drug; it has no cardiotoxicity, no arrhythmia, no addiction, no respiratory depression, and no serious gastrointestinal reactions.

[0025] 2. Limitations: It can only be administered via local injection and requires professional medical personnel to operate. It cannot be taken orally, injected intravenously, or used by oneself. It needs to be stored at 2℃~8℃ protected from light and refrigerated. If left at room temperature for too long, it is prone to gelation, which will affect the injection operation. Its onset of action is slower than that of ordinary water injections. It is more suitable for chronic pain control and is not suitable as an emergency medication for acute and severe pain.

Claims

1. A low-irritation, high-safety benzoyl aconitine thermosensitive analgesic gel injection, characterized in that, The injection solution is a local injection preparation, and based on the volume of a unit preparation, it contains the following components: (1) Analgesic active ingredient: benzoyl aconitine or its pharmaceutically acceptable salt or ester, with a mass-volume concentration of 0.01% to 0.05%; (2) Cardioprotective system: composed of a subanesthetic dose of lidocaine, glycyrrhizic acid monoammonium salt, and magnesium sulfate; wherein the mass-volume concentration of lidocaine is 0.02% to 0.1%, the mass-volume concentration of glycyrrhizic acid monoammonium salt is 0.08% to 0.12%, and the mass-volume concentration of magnesium sulfate is 0.12% to 0.18%; (3) Thermosensitive gel matrix: poloxamer 407, with a mass-volume concentration of 18% to 22%; (4) Solubilizer: selected from one or more of propylene glycol, polyethylene glycol 400, and glycerin, with a mass-volume concentration of 2% to 8%; (5) Antioxidant: selected from one or more of vitamin C, sodium bisulfite, and sodium metabisulfite, with a mass-volume concentration of 0.01% to 0.05%; (6) Solvent: Water for injection, added to the total volume of the unit preparation; The injection solution meets the following key parameters: pH value is 5.5 to 6.5; It is a clear, flowable liquid at 20℃ to 28℃ and can be smoothly injected through a 25G to 27G injection needle; It forms a semi-solid hydrogel within 1 to 5 minutes at 35℃ to 39℃; The subanesthetic dose of lidocaine competitively blocks the myocardial Nav1.5 sodium channel, and together with the cell membrane stabilizing effect of glycyrrhizic acid monoammonium salt and the myocardial electrophysiological regulation effect of magnesium sulfate, it forms a triple cardiac protection system, reducing the cardiotoxicity of benzoyl aconitine.

2. The thermosensitive analgesic gel injection solution according to claim 1, characterized in that, The volume of the unit preparation is 0.5 mL to 5 mL, preferably 2 mL; the mass ratio of glycyrrhizic acid monoammonium salt to benzoyl aconitine is (4 to 6):1, the mass ratio of magnesium sulfate to benzoyl aconitine is (6 to 8):1; the mass ratio of lidocaine to benzoyl aconitine is (2.25 to 2.75):1, preferably 2.5:

1.

3. The thermosensitive analgesic gel injection solution according to claim 2, characterized in that, Each 1 mL of the injection solution comprises: benzoyl aconitine 0.18–0.22 mg, lidocaine 0.45–0.55 mg, glycyrrhizic acid monoammonium salt 0.9–1.1 mg, magnesium sulfate 1.35–1.65 mg, poloxamer 407 180–220 mg, propylene glycol 0.045–0.055 mL, vitamin C 0.18–0.22 mg, with the balance being water for injection; preferably, each 1 mL comprises: benzoyl aconitine 0.19–0.21 mg, lidocaine 0.48–0.52 mg, glycyrrhizic acid monoammonium salt 0.95–1.05 mg, magnesium sulfate 1.42–1.58 mg, poloxamer 407 190–210 mg, propylene glycol 0.048–0.052 mL, vitamin C 0.19–0.21 mg. mg, with the remainder being water for injection; more preferably, each 1 mL contains: benzoyl aconitine 0.2 mg, lidocaine 0.5 mg, glycyrrhizic acid monoammonium salt 1.0 mg, magnesium sulfate 1.5 mg, poloxamer 407 200 mg, propylene glycol 0.05 mL, vitamin C 0.2 mg, with the remainder being water for injection.

4. The thermosensitive analgesic gel injection solution according to claim 2, characterized in that, Each 2 mL of the injection solution comprises: benzoyl aconitine 0.36–0.44 mg, lidocaine 0.9–1.1 mg, glycyrrhizic acid monoammonium salt 1.8–2.2 mg, magnesium sulfate 2.7–3.3 mg, poloxamer 407 360–440 mg, propylene glycol 0.09–0.11 mL, vitamin C 0.36–0.44 mg, with the balance being water for injection; preferably, each 2 mL comprises: benzoyl aconitine 0.38–0.42 mg, lidocaine 0.95–1.05 mg, glycyrrhizic acid monoammonium salt 1.9–2.1 mg, magnesium sulfate 2.85–3.15 mg, poloxamer 407 380–420 mg, propylene glycol 0.095–0.105 mL, vitamin C 0.38–0.42 mg, with the balance being water for injection; more preferably, each 2 mL The solution contains: benzoyl aconitine 0.4 mg, lidocaine 1.0 mg, glycyrrhizic acid monoammonium salt 2.0 mg, magnesium sulfate 3.0 mg, poloxamer 407 400 mg, propylene glycol 0.1 mL, vitamin C 0.4 mg, and water for injection to a final volume of 2.0 mL. The pH of the solution is 6.

0. It forms a semi-solid hydrogel within 3 minutes at 37°C. The uniformity of benzoyl aconitine content is ≤±2%.

5. A drug formulation method for reducing the cardiotoxicity of benzoyl aconitine, characterized in that, A combination of lidocaine at a subanesthetic dose and benzoyl aconitine is used, wherein the lidocaine mass-volume concentration is ≤0.055%, and the lidocaine is at a non-anesthetic dose, exerting only a cardiotoxic antagonistic effect; simultaneously, glycyrrhizic acid monoammonium salt and magnesium sulfate are added to form a triple cardioprotective system with lidocaine, wherein the mass ratio of glycyrrhizic acid monoammonium salt to benzoyl aconitine is (4-6):1, and the mass ratio of magnesium sulfate to benzoyl aconitine is (6-8):

1.

6. A method for preparing a benzoyl aconitine thermosensitive analgesic gel injection according to any one of claims 1 to 4, characterized in that, Includes the following steps: (1) Gel matrix dissolution: Under low temperature conditions of 0℃~10℃, add the prescribed amount of poloxamer 407 to an appropriate amount of water for injection, and stir at a stirring rate of 200~500r / min for 2~6 hours until completely dissolved to obtain a clear gel matrix solution; (2) Excipient premixing: Add the prescribed amount of solubilizer and antioxidant to the gel matrix solution obtained in step (1), and stir at low temperature of 0℃~10℃ for 10~20 minutes to mix evenly to obtain a first mixed solution; (3) Cardiac protection system addition: Add the prescribed amount of lidocaine, glycyrrhizic acid monoammonium salt, and magnesium sulfate to the first mixed solution obtained in step (2) in sequence, and stir at low temperature of 0℃~10℃ until completely dissolved to obtain a second mixed solution; (4) Active ingredient addition: Add the prescribed amount of benzoyl aconitine to the second mixed solution obtained in step (3), and stir at low temperature of 0℃~10℃ for 15~30 minutes until evenly dissolved to obtain a third mixed solution; (5) pH Adjustment and volume determination: Adjust the pH of the third mixed solution to 5.5-6.5 with 0.1 mol / L hydrochloric acid solution or sodium hydroxide solution, add water for injection to the total volume of the unit preparation, and stir to obtain the drug solution; (6) Sterilization and filling: The drug solution obtained in step (5) is filtered through a 0.22μm microporous membrane for sterilization, and then filled into sterile injection bottles in a Class 100 clean environment to obtain the finished product; The finished product is stored in the dark at 2℃~8℃, and the degradation rate of benzoyl aconitine is ≤5% within the shelf life, and the temperature-sensitive properties are not significantly changed.

7. The use of the benzoyl aconitine thermosensitive analgesic gel injection according to any one of claims 1 to 4 in the preparation of a non-addictive local analgesic for local injection to treat severe chronic pain and reduce the cardiotoxicity of benzoyl aconitine, wherein the lidocaine exerts its cardiotoxicity antagonistic effect at a subanesthetic dose.

8. The application according to claim 7, characterized in that, The drug is used to treat neuropathic pain, cold-dampness obstruction type neck, shoulder, waist and leg pain, joint pain or soft tissue injury pain; the drug is only for local targeted administration, excluding intravenous injection and intramuscular injection routes, and the local targeted administration method is one or more of local pain point injection, acupoint injection, periarticular injection or fascia layer injection; the injection pain is mild or less, only manifested as a brief soreness at the injection site, without obvious stinging, burning or distending pain, and has no addictive or dependent properties, and does not produce respiratory depression, serious gastrointestinal adverse reactions or cardiotoxic adverse reactions.