Compound lidocaine external solution and preparation method thereof

Abstract

The application provides a compound lidocaine external solution and a preparation method thereof, and belongs to the technical field of external medicines. The compound lidocaine external solution comprises the following components in percentage by mass: lidocaine-dicaine co-crystal 4-10%, 15-hydroxystearic acid polyethylene glycol ester 2-8%, soybean phosphatidylcholine 2-8%, anhydrous ethanol 0.5-4%, antioxidant 0.05-0.1%, and water in an appropriate amount. The application takes lidocaine and dicaine as active ingredients, adopts a specific method to prepare the lidocaine-dicaine co-crystal, and prepares the compound lidocaine external solution through high-speed dispersion, shear emulsification and high-pressure homogenization under the synergistic effect of 15-hydroxystearic acid polyethylene glycol ester and soybean phosphatidylcholine. The prepared compound lidocaine external solution has good quality stability, and the drug has a fast onset and a long drug effect maintenance time.

Description

Technical Field

[0001] This invention relates to the field of topical medicine technology, specifically to a compound lidocaine topical solution and its preparation method. Background Technology

[0002] Local anesthetics (LA) are a class of drugs that reversibly block the generation and transmission of sensory nerve impulses at the site of application. In recent years, LA has been increasingly used for postoperative analgesia due to its significant analgesic effect and fewer complications. Lidocaine, also known as xylocaine, is currently the most widely used LA, possessing advantages such as rapid onset, strong and long-lasting effect, strong penetration, and a relatively wide safety margin.

[0003] Currently, local anesthetics are administered via surface anesthesia, local infiltration anesthesia, regional block anesthesia, and nerve block anesthesia. Surface anesthesia involves applying a highly penetrating local anesthetic to the skin surface, allowing it to penetrate and block nerve endings beneath the skin, thus producing anesthesia. Surface anesthetic preparations typically include ointments, plasters, creams, poultices, patches, and lotions. However, ointments and patches often have drawbacks such as slow onset of action and less than ideal transdermal penetration. For example, patent CN115068411A discloses a lidocaine-tetracaine compound cream containing the following components: lidocaine, tetracaine, polyvinyl alcohol, white mineral oil, methylparaben, propylparaben, emulsifier, and anhydrous calcium hydrogen phosphate. This lidocaine-tetracaine compound cream has the advantage of stable quality, but it contains a large amount of lubricating and thickening components, which is detrimental to the release of the active ingredients lidocaine and tetracaine, leading to a prolonged onset of action. Summary of the Invention

[0004] To address the shortcomings of the existing technologies, this invention provides a compound lidocaine topical solution with good transdermal effect and rapid onset of action, as well as its preparation method.

[0005] To achieve the above objectives, the specific technical solution of the present invention is as follows:

[0006] Compound lidocaine topical solution comprises the following components by weight percentage: lidocaine-tetracaine cocrystal 4%~10%, 15-hydroxystearic acid polyethylene glycol ester 2%~8%, soybean phosphatidylcholine 2%~8%, anhydrous ethanol 0.5%~4%, antioxidant 0.05%~0.1%, and appropriate amount of water.

[0007] To address the problem of poor transdermal efficacy in existing compound lidocaine topical medications, this invention uses lidocaine and tetracaine as co-active ingredients and prepares lidocaine-tetracaine co-crystals using a specific method. With the synergistic effect of 15-hydroxystearic acid polyethylene glycol ester and soybean phosphatidylcholine, the compound lidocaine topical solution of this invention exhibits advantages such as good transdermal efficacy, rapid onset of action, and long duration of effect.

[0008] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 6% lidocaine-tetracaine cocrystal, 4% polyethylene glycol 15-hydroxystearate, 6% soybean phosphatidylcholine, 2% anhydrous ethanol, 0.1% antioxidant, and an appropriate amount of water.

[0009] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 4% lidocaine-tetracaine cocrystal, 4% polyethylene glycol 15-hydroxystearate, 6% soybean phosphatidylcholine, 4% anhydrous ethanol, 0.1% antioxidant, and an appropriate amount of water.

[0010] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 6% lidocaine-tetracaine cocrystal, 4% polyethylene glycol 15-hydroxystearate, 6% soybean phosphatidylcholine, 4% anhydrous ethanol, 0.1% antioxidant, and appropriate amount of water.

[0011] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 8% lidocaine-tetracaine cocrystal, 4% 15-hydroxystearic acid polyethylene glycol ester, 6% soybean phosphatidylcholine, 4% anhydrous ethanol, 0.1% antioxidant, and appropriate amount of water.

[0012] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 10% lidocaine-tetracaine cocrystal, 4% 15-hydroxystearic acid polyethylene glycol ester, 6% soybean phosphatidylcholine, 4% anhydrous ethanol, 0.1% antioxidant, and appropriate amount of water.

[0013] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 6% lidocaine-tetracaine cocrystal, 8% 15-hydroxystearic acid polyethylene glycol ester, 2% soybean phosphatidylcholine, 4% anhydrous ethanol, 0.1% antioxidant, and appropriate amount of water.

[0014] Preferably, the compound lidocaine topical solution comprises the following components by mass percentage: 6% lidocaine-tetracaine cocrystal, 2% 15-hydroxystearic acid polyethylene glycol ester, 8% soybean phosphatidylcholine, 4% anhydrous ethanol, 0.1% antioxidant, and appropriate amount of water.

[0015] Preferably, the method for preparing the lidocaine-tetracaine eutectic includes the following steps: mixing lidocaine, tetracaine, citric acid and a solvent, heating and then cooling to obtain the lidocaine-tetracaine eutectic.

[0016] Preferably, the mass ratio of docaine, tetracaine, and citric acid is (1~1.8):1:(0.05~0.1).

[0017] More preferably, the mass ratio of docaine, tetracaine, and citric acid is 1.4:1:0.05.

[0018] Preferably, the heating temperature is 40~70 ℃ and the heating time is 1~3 h.

[0019] Preferably, the solvent is ethanol or methanol.

[0020] Preferably, the purity of the soybean phosphatidylcholine is ≥94%.

[0021] Preferably, the compound lidocaine topical solution further includes the following components by mass percentage: 0.5%~4% ethanol and 0.05%~0.1% antioxidant.

[0022] Preferably, the antioxidant is potassium sorbate.

[0023] The present invention also provides a method for preparing the compound lidocaine topical solution, comprising the following steps:

[0024] S1. Soybean phosphatidylcholine is dissolved in ethanol to obtain mixture I. 15-hydroxystearic acid polyethylene glycol ester is mixed with water to obtain mixture II. Mix mixture I and mixture II are mixed evenly to obtain mixture III.

[0025] S2. Add lidocaine-tetracaine cocrystals to mixture III, mix thoroughly, disperse by shearing, and adjust the pH to 8.0~10.0 to obtain mixture IV;

[0026] S3. Add the antioxidant to mixture IV, homogenize under high pressure to obtain compound lidocaine external solution;

[0027] Alternatively, it may include the following steps:

[0028] S1. Soybean phosphatidylcholine was dissolved in ethanol, and then 15-hydroxystearic acid polyethylene glycol ester and lidocaine-tetracaine cocrystal were added and mixed at 40 °C for 15 min to obtain mixture I.

[0029] S2. Mix mixture I with water until homogeneous, disperse by shearing, and adjust the pH to 8.0~10.0 to obtain mixture II;

[0030] S3. Add the antioxidant to mixture II and homogenize under high pressure to obtain compound lidocaine external solution.

[0031] Preferably, the shear dispersion temperature is 30~50 ℃, the rotation speed is 8000~12000 rpm, and the time is 30~120 min.

[0032] More preferably, the shear dispersion temperature is 40 ℃, the rotation speed is 10000 rpm, and the time is 60 min.

[0033] Preferably, the reagent used to adjust the pH is a hydrochloric acid solution or a sodium hydroxide solution.

[0034] Preferably, the high-pressure homogenization is carried out at a temperature of 20-50°C, a pressure of 300-800 bar, and 3-9 times.

[0035] More preferably, the high-pressure homogenization is carried out at a temperature of 30 °C, a pressure of 600 bar, and a number of cycles of 5.

[0036] Preferably, the average particle size of the compound lidocaine topical solution is 40-80 nm.

[0037] Compared with the prior art, the advantages of the present invention are:

[0038] 1. The present invention uses lidocaine-tetracaine cocrystal as the active ingredient. With the synergistic effect of 15-hydroxystearic acid polyethylene glycol ester and soybean phosphatidylcholine, the prepared compound lidocaine topical solution has good transdermal effect, fast onset of action and long duration of efficacy.

[0039] 2. This invention uses high-speed shear dispersion and high-pressure homogenization technology to control the solution particle size to between 50 and 70 nm. The smaller solution particle size can effectively improve the transdermal penetration speed of the drug, thereby accelerating the onset time and achieving a rapid analgesic effect. Detailed Implementation

[0040] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0041] The present invention provides a compound lidocaine external solution comprising the following components by mass percentage: lidocaine-tetracaine cocrystal 4%~10%, 15-hydroxystearic acid polyethylene glycol ester 2%~8%, and soybean phosphatidylcholine 2%~8%.

[0042] The method for preparing the lidocaine-tetracaine eutectic includes the following steps: mixing lidocaine, tetracaine, citric acid and a solvent, heating and then cooling to obtain the lidocaine-tetracaine eutectic.

[0043] In some examples, the mass ratio of docaine, tetracaine, and citric acid is (1~1.8):1:(0.05~0.1).

[0044] In some examples, the heating temperature is 40~70 °C and the time is 1~3 h.

[0045] In some examples, the solvent is ethanol or methanol.

[0046] In some examples, the purity of the soybean phosphatidylcholine is ≥94%; in the following specific embodiments, the purity of the soybean phosphatidylcholine is 98%; and the antioxidant is potassium sorbate.

[0047] Examples 1-4

[0048] The compound lidocaine topical solution comprises the following components by weight percentage: lidocaine-tetracaine cocrystal 6%, 15-hydroxystearic acid polyethylene glycol ester 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 2%, antioxidant 0.1%, and water 81.9%.

[0049] The lidocaine-tetracaine cocrystal is prepared as follows: lidocaine, tetracaine, and citric acid are mixed evenly with ethanol (the mass-to-volume ratio of lidocaine to ethanol is 1:3 g / mL), heated to 50 °C in an open container, stirred for 1 h, and then cooled to obtain the lidocaine-tetracaine cocrystal. The mass ratio of lidocaine, tetracaine, and citric acid is shown in Table 1.

[0050] The preparation method of the compound lidocaine external solution is as follows:

[0051] S1. Dissolve soybean phosphatidylcholine in anhydrous ethanol to obtain mixture I, mix 15-hydroxystearic acid polyethylene glycol ester and water to obtain mixture II, and mix mixture I and mixture II evenly to obtain mixture III.

[0052] S2. Add lidocaine-tetracaine cocrystal to mixture III, mix thoroughly, disperse at 40 ℃ and 10000 rpm for 60 min, adjust pH to 10 with 0.1 mol / L sodium hydroxide solution, and stir for 30 min to obtain mixture IV;

[0053] S3. Add potassium sorbate to mixture IV and homogenize under high pressure five times at 30 ℃ and 600 bar to obtain compound lidocaine external solution.

[0054] Table 1: Mass ratio of lidocaine, tetracaine, and citric acid in Examples 1-4

[0055]

[0056] Examples 5-10

[0057] Compound lidocaine topical solution comprises the following components: lidocaine-tetracaine cocrystal, polyethylene glycol 15-hydroxystearate, soybean phosphatidylcholine, anhydrous ethanol, antioxidant, and water. The mass percentages of each component are shown in Table 2.

[0058] The lidocaine-tetracaine cocrystal is prepared as follows: lidocaine, tetracaine, and citric acid are mixed with ethanol at a mass ratio of 1.4:1:0.05 (the mass-volume ratio of lidocaine to ethanol is 1:3 g / mL). The mixture is heated to 50 °C and stirred for 1 h in an open container, then cooled to obtain the lidocaine-tetracaine cocrystal.

[0059] The preparation method of the compound lidocaine external solution is as follows:

[0060] S1. Dissolve soybean phosphatidylcholine in anhydrous ethanol to obtain mixture I, mix 15-hydroxystearic acid polyethylene glycol ester and water to obtain mixture II, and mix mixture I and mixture II evenly to obtain mixture III.

[0061] S2. Add lidocaine-tetracaine cocrystal to mixture III, mix thoroughly, disperse at 40 ℃ and 10000 rpm for 60 min, adjust pH to 10 with 0.1 mol / L sodium hydroxide solution, and stir for 30 min to obtain mixture IV;

[0062] S3. Add potassium sorbate to mixture IV and homogenize under high pressure five times at 30 ℃ and 600 bar to obtain compound lidocaine external solution.

[0063] Table 2: Mass percentage of each component in the compound lidocaine topical solution in Examples 5-10

[0064]

[0065] Comparative Example 1

[0066] The compound lidocaine topical solution comprises the following components by weight percentage: lidocaine-tetracaine-citric acid mixture 6%, 15-hydroxystearic acid polyethylene glycol ester 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 2%, antioxidant 0.1%, and water 81.9%.

[0067] The lidocaine-tetracaine-citric acid mixture is prepared as follows: lidocaine, tetracaine and citric acid are mixed evenly in a mass ratio of 1.4:1:0.05 to obtain the lidocaine-tetracaine-citric acid mixture.

[0068] The preparation method of the compound lidocaine external solution is as follows:

[0069] S1. Dissolve soybean phosphatidylcholine in anhydrous ethanol to obtain mixture I, mix 15-hydroxystearic acid polyethylene glycol ester and water to obtain mixture II, and mix mixture I and mixture II evenly to obtain mixture III.

[0070] S2. Add the lidocaine-tetracaine-citric acid mixture to mixture III, mix well, disperse at 40 ℃ and 10000 rpm for 60 min, adjust the pH to 10 with 0.1 mol / L sodium hydroxide solution, and stir for 30 min to obtain mixture IV;

[0071] S3. Add potassium sorbate to mixture IV and homogenize under high pressure five times at 30 ℃ and 600 bar to obtain compound lidocaine external solution.

[0072] Comparative Example 2

[0073] The compound lidocaine topical solution comprises the following components by weight percentage: lidocaine-tetracaine mixture 6%, 15-hydroxystearic acid polyethylene glycol 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 2%, antioxidant 0.1%, and water 81.9%.

[0074] The lidocaine-tetracaine mixture is prepared as follows: lidocaine and tetracaine are mixed with ethanol at a mass ratio of 1.5:1 (the mass-volume ratio of lidocaine to ethanol is 1:3 g / mL), heated to 50 °C in an open container and stirred for 1 h, then cooled to obtain the lidocaine-tetracaine mixture.

[0075] The preparation method of the compound lidocaine external solution is as follows:

[0076] S1. Dissolve soybean phosphatidylcholine in anhydrous ethanol to obtain mixture I, mix 15-hydroxystearic acid polyethylene glycol ester and water to obtain mixture II, and mix mixture I and mixture II evenly to obtain mixture III.

[0077] S2. Add lidocaine-tetracaine cocrystal to mixture III, mix thoroughly, disperse at 40 ℃ and 10000 rpm for 60 min, adjust pH to 10 with 0.1 mol / L sodium hydroxide solution, and stir for 30 min to obtain mixture IV;

[0078] S3. Add potassium sorbate to mixture IV and homogenize under high pressure five times at 30 ℃ and 600 bar to obtain compound lidocaine external solution.

[0079] Comparative Example 3

[0080] The compound lidocaine topical solution comprises the following components by weight percentage: lidocaine-tetracaine cocrystal 6%, 10% polyethylene glycol 15-hydroxystearate, 2% anhydrous ethanol, 0.1% antioxidant, and 81.9% water.

[0081] The preparation method of the compound lidocaine external solution is as follows:

[0082] S1. Dissolve 15-hydroxystearic acid polyethylene glycol ester (6%) in anhydrous ethanol to obtain mixture I. Mix 15-hydroxystearic acid polyethylene glycol ester (4%) with water to obtain mixture II. Mix mixture I and mixture II evenly to obtain mixture III.

[0083] S2. Add lidocaine-tetracaine cocrystal to mixture III, mix thoroughly, disperse at 40 ℃ and 10000 rpm for 60 min, adjust pH to 10 with 0.1 mol / L sodium hydroxide solution, and stir for 30 min to obtain mixture IV;

[0084] S3. Add potassium sorbate to mixture IV and homogenize under high pressure five times at 30 ℃ and 600 bar to obtain compound lidocaine external solution.

[0085] Comparative Example 4

[0086] The compound lidocaine topical solution comprises the following components by weight percentage: lidocaine-tetracaine cocrystal 6%, soybean phosphatidylcholine 10%, anhydrous ethanol 2%, antioxidant 0.1%, and water 81.9%.

[0087] The preparation method of the compound lidocaine external solution is as follows:

[0088] S1. Dissolve soybean phosphatidylcholine (6%) in anhydrous ethanol to obtain mixture I. Mix soybean phosphatidylcholine (4%) with water to obtain mixture II. Mix mixture I and mixture II evenly to obtain mixture III.

[0089] S2. Add lidocaine-tetracaine cocrystal to mixture III, mix thoroughly, disperse at 40 ℃ and 10000 rpm for 60 min, adjust pH to 10 with 0.1 mol / L sodium hydroxide solution, and stir for 30 min to obtain mixture IV;

[0090] S3. Add potassium sorbate to mixture IV and homogenize under high pressure five times at 30 ℃ and 600 bar to obtain compound lidocaine external solution.

[0091] Average particle size detection

[0092] The average particle size of the compound lidocaine topical solutions prepared in Examples 1-10 and Comparative Examples 1-4 was determined using a particle size analyzer. The results are shown in Table 3.

[0093] Table 3: Average particle size detection results of compound lidocaine topical solution

[0094]

[0095] As shown in Table 3, the average particle size of the compound lidocaine topical solution prepared by this invention is approximately 60 nm. In the preparation of the lidocaine-tetracaine eutectic, when the mass ratio of lidocaine, tetracaine, and citric acid is 1.4:1:0.05, the average particle size of the compound lidocaine topical solution is relatively small. In contrast, in Comparative Examples 1-4, the average particle size of the compound lidocaine topical solution prepared after changing the formulation is relatively large.

[0096] 1. Stability testing

[0097] The compound lidocaine topical solutions prepared in Examples 1-10 and Comparative Examples 1-4 were placed in an environment with a temperature of 25 ℃±2 ℃ and a relative humidity of 65±5% for 1 month. The appearance of the samples was observed, and the test results are shown in Table 4.

[0098] Table 4: Stability test results of compound lidocaine topical solution

[0099]

[0100] As shown in Table 4, the compound lidocaine topical solution prepared in this invention did not show significant changes in appearance after being stored at 25 ℃±2 ℃ and 65±5% relative humidity for one month, indicating good quality stability. However, the compound lidocaine topical solutions of Comparative Examples 1-4 showed sample stratification or demulsification after being stored at 25 ℃±2 ℃ and 65±5% relative humidity for one month, indicating poor quality stability. These experimental results demonstrate that the compound lidocaine topical solution prepared in this invention has stable quality, and the compound formulation and high-pressure homogenization process have a synergistic effect on the quality stability of the topical solution.

[0101] 2. Drug efficacy evaluation

[0102] The efficacy of compound lidocaine topical solutions prepared in Examples 1-10 and Comparative Examples 1-4 was tested using a guinea pig acupuncture reaction model. Acupuncture was performed on the administration site at different times after administration to observe whether the guinea pigs had a stinging reaction, so as to determine the onset time of the drug. After the drug took effect, the administration device was removed and the duration of drug efficacy was further examined. The efficacy evaluation results are shown in Table 5.

[0103] Table 5: Efficacy Evaluation Results of Compound Lidocaine Topical Solution

[0104]

[0105] As shown in Table 5, the compound lidocaine topical solution of the present invention has a fast onset time and a long duration of efficacy; while the compound lidocaine topical solutions of Comparative Examples 1 to 4 have a significantly longer onset time, a slower onset time, and a shorter duration of efficacy.

[0106] In summary, this invention uses lidocaine and tetracaine as active ingredients and prepares lidocaine-tetracaine cocrystals using a specific method. The lidocaine-tetracaine cocrystals are then dispersed at high speed, sheared emulsified, and homogenized under high pressure to prepare a compound lidocaine topical solution. The prepared compound lidocaine topical solution has good quality stability, a short onset time, and a long duration of efficacy.

[0107] The above detailed embodiments describe the implementation of the present invention; however, the present invention is not limited to the specific details described in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. A compound lidocaine external solution, characterized in that, The product comprises the following components by weight percentage: lidocaine-tetracaine cocrystal 4%~10%, 15-hydroxystearic acid polyethylene glycol ester 2%~8%, soybean phosphatidylcholine 2%~8%, anhydrous ethanol 0.5%~4%, antioxidant 0.05%~0.1%, and water as needed.

2. The compound lidocaine topical solution according to claim 1, characterized in that, The compound lidocaine topical solution comprises the following components by mass percentage: lidocaine-tetracaine cocrystal 6%, 15-hydroxystearic acid polyethylene glycol ester 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 2%, antioxidant 0.1%, and appropriate amount of water.

3. The compound lidocaine external solution according to claim 1, characterized in that, The compound lidocaine topical solution comprises the following components by mass percentage: lidocaine-tetracaine cocrystal 4%, 15-hydroxystearic acid polyethylene glycol ester 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 4%, antioxidant 0.1%, and appropriate amount of water.

4. The compound lidocaine topical solution according to claim 1, characterized in that, The compound lidocaine topical solution comprises the following components by mass percentage: lidocaine-tetracaine cocrystal 6%, 15-hydroxystearic acid polyethylene glycol ester 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 4%, antioxidant 0.1%, and appropriate amount of water.

5. The compound lidocaine topical solution according to claim 1, characterized in that, The compound lidocaine topical solution comprises the following components by mass percentage: lidocaine-tetracaine cocrystal 8%, 15-hydroxystearic acid polyethylene glycol ester 4%, soybean phosphatidylcholine 6%, anhydrous ethanol 4%, antioxidant 0.1%, and appropriate amount of water.

6. The compound lidocaine external solution according to claim 1, characterized in that, The method for preparing the lidocaine-tetracaine eutectic, The process includes the following steps: mixing lidocaine, tetracaine, citric acid, and a solvent, heating, and then cooling to obtain a lidocaine-tetracaine eutectic.

7. The compound lidocaine topical solution according to claim 6, characterized in that, The mass ratio of docaine, tetracaine, and citric acid is (1~1.8):1:(0.05~0.1).

8. The method for preparing the compound lidocaine topical solution according to any one of claims 1 to 7, characterized in that, Includes the following steps: S1. Mixture I, which is a mixture of soybean phosphatidylcholine dissolved in ethanol, and mixture II, which is a mixture of 15-hydroxystearic acid polyethylene glycol ester and water, and mixture III, which is a mixture of mixture I and mixture II. S2. Add lidocaine-tetracaine cocrystals to mixture III, mix thoroughly, disperse by shearing, and adjust the pH to 8.0~10.0 to obtain mixture IV; S3. Add the antioxidant to the mixture IV, and homogenize under high pressure to obtain the compound lidocaine topical solution; Alternatively, it may include the following steps: S1. Soybean phosphatidylcholine was dissolved in ethanol, and then 15-hydroxystearic acid polyethylene glycol ester and lidocaine-tetracaine cocrystal were added and mixed evenly to obtain mixture I. S2. Mix mixture I with water, disperse by shearing, and adjust the pH to 8.0~10.0 to obtain mixture II; S3. Add the antioxidant to mixture II and homogenize under high pressure to obtain compound lidocaine external solution.

9. The method for preparing the compound lidocaine external solution according to claim 8, characterized in that, The shear dispersion is performed at a temperature of 30-50 °C, a rotation speed of 8000-12000 rpm, and a time of 30-120 min.

10. The method for preparing the compound lidocaine external solution according to claim 8, characterized in that, The high-pressure homogenization is carried out at a temperature of 20~50 ℃, a pressure of 300~800 bar, and 3~9 times.

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