Surface anesthetic with oral mucosa adhesion, salivation resistance and taste improvement effects and preparation method thereof

Abstract

The invention provides a surface anesthetic with oral mucosa adhesiveness, salivation resistance and taste improvement effects and a preparation method of the surface anesthetic, and belongs to the technical field of anesthetics. The surface anesthetic provided by the invention comprises tetracaine hydrochloride, glycopyrronium bromide and an auxiliary material, and the auxiliary material comprises a drug entrapment auxiliary material. Compared with caine anesthetics used clinically, the surface anesthetic provided by the invention has multiple functions of salivation resistance, good mucous membrane adhesiveness and improved taste, not only improves the drug effect, but also increases the medication compliance, and has great clinical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of anesthetics, and particularly relates to a surface anesthetic with oral mucosal adhesion, anti-salivation and mouthfeel improving effects and a preparation method thereof. Background Art

[0002] Tetracaine hydrochloride is an ester local anesthetic with high fat solubility and strong penetration. Its toxicity and anesthetic effect are higher than lidocaine. However, due to its high toxicity, its clinical use is relatively limited. Certain oral diseases 、 In the clinical treatment of ENT diseases, ophthalmology and tracheobronchoscopy, the use of cacine-based anesthetics for local anesthesia in the oral cavity or trachea is required. However, such anesthetics have a strong bitter taste, which leads to poor compliance during the use of such drugs. In addition, due to the continuous secretion of oral saliva, such anesthetics are easily diluted and metabolized. Therefore, the development of a surface anesthetic with oral mucosal adhesion and improved taste is of great clinical significance. Summary of the invention

[0003] In view of this, in order to solve the clinical medication pain points of the existing oral anesthetics, which are bitter, easily diluted and metabolized by oral secretions, one of the purposes of the present invention is to provide a topical anesthetic with oral mucosal adhesion, anti-salivation effect and improved taste. The second purpose of the present invention is to provide a topical anesthetic that can improve the compliance of oral spray medication and has oral mucosal adhesion and anti-salivation effect.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The invention provides a topical anesthetic, which comprises tetracaine hydrochloride, glycopyrrolate and auxiliary materials, wherein the auxiliary materials comprise drug-carrying auxiliary materials.

[0006] Preferably, the mass ratio of tetracaine hydrochloride, glycopyrrolate and drug encapsulating excipient is (3-5):(3-30):(25-55).

[0007] Preferably, the drug encapsulation excipients include phospholipids, cholesterol and amphiphilic lipids.

[0008] Preferably, the mass ratio of phospholipid, cholesterol and amphiphilic lipid is (20-70):(20-60):(1-5).

[0009] Preferably, the phospholipid includes at least one of soybean lecithin, lecithin, hydrogenated soybean lecithin, egg yolk lecithin, DLPC, DEPC, DPPS, DOPE, EPG, DPPG, DOPC, DPPC, DMPC and POPC.

[0010] Preferably, the amphiphilic lipid includes at least one of PEG-DMG, PEG2000-c-DMG, PEG-c-DMA, DSPE-PEG, PEG-PE, Tween-20, Tween-80, DAA and PEG-c-DOMG.

[0011] Preferably, the auxiliary materials further include taste improving auxiliary materials, and the taste improving auxiliary materials include at least one of sorbitol, menthol, sucrose, mannose, glucose, sucralose, citric acid, sodium chloride, sodium carbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate.

[0012] Preferably, the final concentration of the taste improving auxiliary material is preferably 5 mg / mL.

[0013] Preferably, the dosage form of the topical anesthetic is a spray preparation.

[0014] The present invention also provides a method for preparing the above-mentioned topical anesthetic, which comprises a microfluidic method, a high-pressure homogenization method or a microfluidic method; the microfluidic method comprises the following steps: dissolving tetracaine hydrochloride, glycopyrrolate and a drug-encapsulating auxiliary material in anhydrous ethanol to obtain an ethanol phase, using a microfluidic device, setting the ethanol phase flow rate to 3 mL / min, and the purified water flow rate to 9 mL / min for mixing, and using purified water for dialyzing to remove ethanol to obtain the topical anesthetic.

[0015] Beneficial effects of the present invention:

[0016] The present invention aims at the disadvantage of tetracaine hydrochloride being relatively toxic. By regulating the composition of the drug-carrying auxiliary material liposome, the present invention enables the drug to penetrate the mucosa and release slowly, thereby ensuring that the local anesthetic tetracaine hydrochloride is not removed by the saliva secreted by the oral cavity, and ensuring that the tetracaine hydrochloride is slowly released, thereby avoiding the toxic and side effects caused by the rapid absorption of the drug. Compared with the caine anesthetics used in clinical practice, the topical anesthetic provided by the present invention has multiple functions of anti-salivation, good mucosal adhesion, and improved taste, thereby improving the efficacy and increasing the compliance of the drug, and having great clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is a particle size diagram of the liposomes obtained in Example 1;

[0018] Figure 2 This is the image of liposome endocytosis marked by fluorescent staining in Example 2;

[0019] Figure 3 This is a particle size diagram of the drug-loaded liposomes containing a taste-masking agent obtained in Example 3;

[0020] Figure 4 This is a particle size diagram of the topical anesthetic spray preparation obtained in Example 4;

[0021] Figure 5 The particle size diagram of the surface anesthetic prepared by different preparation methods;

[0022] Figure 6 This is a particle size diagram of the topical anesthetic spray preparation obtained in Example 6;

[0023] Figure 7 This is a particle size diagram of the topical anesthetic spray preparation obtained in Example 7;

[0024] Figure 8 This is a particle size diagram of the topical anesthetic spray preparation obtained in Example 8;

[0025] Fig. 9 Diagram for tetracaine release. DETAILED DESCRIPTION

[0026] The invention provides a topical anesthetic, which comprises tetracaine hydrochloride, glycopyrrolate and auxiliary materials, wherein the auxiliary materials comprise drug-carrying auxiliary materials.

[0027] The present invention does not specifically limit the specific sources of tetracaine hydrochloride, glycopyrrolate and excipients, and conventional commercial products in the art can be used. In the present invention, the mass ratio of tetracaine hydrochloride, glycopyrrolate and drug-encapsulated excipients is preferably (3-5): (3-30): (25-55), and more preferably 4: (5-20): (35-40). In the topical anesthetic of the present invention, the final concentration of tetracaine hydrochloride is preferably 0.5 mg / mL to 10 mg / mL, and more preferably 2 mg / mL to 8 mg / mL. In the present invention, the drug-encapsulated excipients preferably include phospholipids, cholesterol and amphiphilic lipids; the mass ratio of phospholipids, cholesterol and amphiphilic lipids is preferably (20-70): (20-60): (1-5), and more preferably (25-50): (30-55): (2-4). In the present invention, the phospholipids preferably include at least one of soybean lecithin, lecithin, hydrogenated soybean lecithin, egg yolk lecithin, DLPC, DEPC, DPPS, DOPE, EPG, DPPG, DOPC, DPPC, DMPC and POPC. The amphiphilic lipids preferably include at least one of PEG-DMG, PEG2000-c-DMG, PEG-c-DMA, DSPE-PEG, PEG-PE, Tween-20, Tween-80, DAA and PEG-c-DOMG.

[0028] The present invention co-encapsulates two drugs of tetracaine hydrochloride and glycopyrrolate by drug encapsulation auxiliary material liposome, thereby eliminating the defects of two drugs being prepared and administered in sequence in clinical practice. When co-encapsulated, tetracaine hydrochloride and glycopyrrolate can co-enter the target tissue, so that the target part simultaneously obtains anesthesia and anti-salivation effects. In addition, the co-encapsulation of the present invention can avoid adverse effects such as liposome precipitation and particle size distribution change brought about when tetracaine hydrochloride liposome and glycopyrrolate liposome are physically mixed. The liposome of the present invention has a sustained release function, and anti-salivation reduces the loss of drugs in the oral cavity. After the liposome enters the mucosa, tetracaine hydrochloride is slowly released, thereby reducing the toxic and side effects caused by too fast absorption during topical administration of tetracaine hydrochloride.

[0029] The present invention co-encapsulates tetracaine hydrochloride and glycopyrrolate by liposomes. As a high-end pharmaceutical preparation, liposomes can encapsulate drug molecules to form nanometer-level drug-loaded particles, so they have a certain taste-masking effect. In addition, the liposomes have a small particle size, a large specific surface area, and a certain affinity with mucosal epithelial cells, so they have a mucosal adhesion effect and can prolong the retention time of the drug in the oral cavity. The present invention optimizes the formula composition of liposomes, and simultaneously encapsulates tetracaine hydrochloride and glycopyrrolate to obtain a multifunctional oral and airway anesthesia spray preparation with anti-salivation, good mucosal adhesion and improved taste.

[0030] In the present invention, the excipients preferably also include taste-improving excipients, and the taste-improving excipients preferably include at least one of sorbitol, menthol, sucrose, mannose, glucose, sucralose, citric acid, sodium chloride, sodium carbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate. In the present invention, the final concentration of the taste-improving excipient is preferably 5 mg / mL. The present invention, by means of the mucosal adhesion effect of liposomes and the combination of taste masking agents, can obtain oral and airway spray anesthetics that meet clinical use, and has the advantages of good medication compliance, anti-salivation and good mucosal adhesion.

[0031] In the present invention, the dosage form of the topical anesthetic is a spray preparation.

[0032] The present invention also provides a method for preparing the above-mentioned topical anesthetic, which preferably includes a microfluidic method, a high-pressure homogenization method or a microfluidic method; the microfluidic method preferably includes the following steps: dissolving tetracaine hydrochloride, glycopyrrolate and a drug-encapsulating auxiliary material in anhydrous ethanol to obtain an ethanol phase, using a microfluidic device, setting the ethanol phase flow rate to 3 mL / min, and the purified water flow rate to 9 mL / min for mixing, and using purified water for dialyzing to remove ethanol to obtain a topical anesthetic.

[0033] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0034] In the following embodiments, unless otherwise specified, all of them are conventional methods.

[0035] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0036] The tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG used in the following examples were purchased from J&K Reagent Company.

[0037] Example 1

[0038] A surface anesthetic is composed of 4 mg of tetracaine hydrochloride, 4 mg of glycopyrrolate and 64 mg of drug-encapsulating excipients, wherein the drug-encapsulating excipients are composed of 30 mg of cholesterol, 30 mg of soybean lecithin and 4 mg of DSPE-PEG.

[0039] The preparation method is as follows: tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG are dissolved in 10 mL of anhydrous ethanol to obtain an ethanol phase, and a microfluidic device is used to set the ethanol phase flow rate to 3 mL / min and the distilled water (also known as purified water) flow rate to 9 mL / min for mixing. Purified water is used for dialysis for 6 hours to remove the solvent ethanol, and liposomes (the liposomes are surface anesthetics) encapsulating tetracaine hydrochloride and glycopyrrolate are obtained. 1 mL of the obtained sample solution is taken, diluted 5 times with purified water, and placed in Dandong BeNano 90Zeta nanoparticle size and zeta potential analyzer to detect its particle size. The particle size distribution is as follows: Figure 1 The particle size of the prepared liposomes is about 170 nm, the PDI is 0.116, and the particle size distribution is uniform.

[0040] Example 2

[0041] A topical anesthetic is composed of 5 mg of tetracaine hydrochloride, 2 mg of glycopyrrolate and 54 mg of drug encapsulation excipients, wherein the drug encapsulation excipients are composed of 25 mg of cholesterol, 25 mg of soybean lecithin and 4 mg of Cy3-DSPE-PEG, wherein the Cy3-DSPE-PEG is purchased from Xi'an Ruixi Biotechnology Co., Ltd.

[0042] The preparation method is as follows: tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and Cy3-DSPE-PEG are dissolved in 10 mL of anhydrous ethanol to obtain an ethanol phase, and a microfluidic device is used to set the ethanol phase flow rate to 3 mL / min and the purified water flow rate to 9 mL / min for mixing. Purified water is dialyzed for 6 hours to remove the solvent ethanol, and Cy3 fluorescently labeled liposomes containing tetracaine hydrochloride and glycopyrrolate are obtained (the liposomes are surface anesthetics).

[0043] Hela cells were cultured at 5×10 4The cells were inoculated at a density of 1000 cells / well in a 24-well plate. After 24 hours, the Cy3 fluorescently labeled liposomes loaded with tetracaine hydrochloride and glycopyrrolate were incubated with Hela cells for 5 minutes, 15 minutes, 30 minutes, and 1 hour. After the incubation, the cells were washed 3 times with PBS, fixed with paraformaldehyde, and then the cell nuclei were stained with DAPI to observe the endocytosis of the liposomes. The fluorescence image of Hela cells is shown in the figure below. Figure 2 As shown in the figure, it can be seen that the red-marked liposomes are taken up by cells in a very short time and can last for 1 hour, which proves that the liposomes of the present invention have the ability of mucosal adhesion and long-term sustained release.

[0044] Example 3

[0045] A surface anesthetic consists of 4 mg of tetracaine hydrochloride, 8 mg of glycopyrrolate, 50 mg of a drug-encapsulating excipient and sucrose, wherein the final concentration of the sucrose is 5 mg / mL, and the drug-encapsulating excipient consists of 25 mg of cholesterol, 20 mg of soybean lecithin and 5 mg of DSPE-PEG.

[0046] The preparation method is as follows: tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG are dissolved in 10 ml of anhydrous ethanol to obtain an ethanol phase, and a microfluidic device is used to set the ethanol phase flow rate to 3 mL / min and the purified water flow rate to 9 mL / min for mixing. Purified water is used for dialysis for 6 hours to remove the solvent ethanol, and sucrose is added to a concentration of 5 mg / mL to obtain a drug-loaded liposome containing a taste masking agent (the drug-loaded liposome containing a taste masking agent is a surface anesthetic), and its particle size distribution is as follows Figure 3 The particle size of the prepared liposomes is about 110 nm, the PDI is 0.172, and the particle size distribution is uniform.

[0047] Example 4

[0048] A surface anesthetic consists of 4 mg of tetracaine hydrochloride, 4 mg of glycopyrrolate, 62 mg of a drug-encapsulating excipient and sucrose, wherein the final concentration of the sucrose is 5 mg / mL, and the drug-encapsulating excipient consists of 40 mg of cholesterol, 20 mg of soybean lecithin and 2 mg of DSPE-PEG.

[0049] The preparation method is as follows: dissolve tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG in 10 ml of anhydrous ethanol to obtain an ethanol phase, use a microfluidic device, set the ethanol phase flow rate to 3 mL / min, and the purified water flow rate to 9 mL / min for mixing. Use purified water to dialyze for 6 hours to remove the solvent ethanol, add sucrose to a concentration of 5 mg / mL, and obtain drug-loaded liposomes containing a taste masking agent (the drug-loaded liposomes containing a taste masking agent are surface anesthetics). Use a vibrating atomization screen to atomize it to obtain a surface anesthetic spray preparation. After collecting the atomized liquid, the particle size is detected. The particle size distribution after atomization is as follows Figure 4 It shows that the liposome surface anesthetic of the present invention can withstand the shear force during atomization, and the particle size of the prepared surface anesthetic spray preparation is about 105nm, the PDI is 0.210, and the particle size distribution is uniform.

[0050] Example 5

[0051] A surface anesthetic consists of 4 mg of tetracaine hydrochloride, 4 mg of glycopyrrolate, 64 mg of a drug-encapsulating excipient and sucrose, wherein the final concentration of the sucrose is 5 mg / mL, and the drug-encapsulating excipient consists of 20 mg of cholesterol, 40 mg of soybean lecithin and 4 mg of DSPE-PEG.

[0052] The following preparation methods were used: microfluidics, high pressure homogenization and microfluidization:

[0053] Microfluidic method: tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG were dissolved in 10 ml of anhydrous ethanol to obtain an ethanol phase, and a microfluidic device was used to set the ethanol phase flow rate to 3 mL / min and the purified water flow rate to 9 mL / min for mixing. The solvent ethanol was dialyzed with purified water for 6 h, and sucrose was added to a concentration of 5 mg / mL to obtain drug-loaded liposomes containing a taste masking agent (the drug-loaded liposomes containing a taste masking agent are surface anesthetics).

[0054] High-pressure homogenization method: Tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG are dissolved in 10 ml of anhydrous ethanol to obtain an ethanol phase, and the ethanol phase is slowly added to the sucrose aqueous solution in the homogenizer to make the final concentration of sucrose 5 mg / mL. After obtaining colostrum, it is homogenized using a high-pressure homogenizer. After constant volume, the drug-loaded liposomes containing a taste-masking agent prepared by the high-pressure homogenizer are obtained (the drug-loaded liposomes containing a taste-masking agent are surface anesthetics).

[0055] Microfluidization method: Tetracaine hydrochloride, glycopyrrolate, cholesterol, soybean lecithin and DSPE-PEG are dissolved in 10 ml of anhydrous ethanol to obtain an ethanol phase, and the ethanol phase is slowly added to the homogenized sucrose aqueous solution to make the final concentration of sucrose 5 mg / mL. After obtaining colostrum, it is homogenized using a microjet, and after constant volume, the drug-loaded liposomes containing a taste-masking agent prepared by microjet are obtained (the drug-loaded liposomes containing a taste-masking agent are surface anesthetics).

[0056] The particle size distribution of the surface anesthetics prepared by the above three different preparation methods is as follows: Figure 5 It shows that the particle size of liposomes prepared by different preparation methods is about 120nm, and the particle size distribution is uniform. The surface anesthetic formulation of the present invention has low requirements on the preparation process, and the particle size can be controlled to be about 120nm.

[0057] Example 6

[0058] A surface anesthetic consists of 4 mg of tetracaine hydrochloride, 4 mg of glycopyrrolate, 62 mg of a drug-encapsulating excipient and sucrose, wherein the final concentration of the sucrose is 5 mg / mL, and the drug-encapsulating excipient consists of 40 mg of cholesterol, 20 mg of soybean lecithin and 2 mg of DSPE-PEG.

[0059] The preparation method is the same as that in Example 4. The particle size is measured after collecting the atomized liquid. The particle size distribution after atomization is as follows: Figure 6 It shows that the particle size of the liposome prepared by the present invention is about 120nm, the PDI is 0.202, the particle size distribution is uniform, and the addition of sucrose has little effect on the particle size of the liposome.

[0060] Example 7

[0061] A topical anesthetic is composed of 4 mg of tetracaine hydrochloride, 4 mg of glycopyrrolate, 62 mg of a drug-encapsulating excipient and maltitol, wherein the final concentration of the maltitol is 5 mg / mL, and the drug-encapsulating excipient is composed of 40 mg of cholesterol, 20 mg of soybean lecithin and 2 mg of DSPE-PEG.

[0062] The preparation method is the same as that in Example 4. The particle size is measured after collecting the atomized liquid. The particle size distribution after atomization is as follows: Figure 7 It shows that the particle size of the liposome prepared by the present invention is about 140nm, the PDI is 0.217, the particle size distribution is uniform, and the addition of maltitol has little effect on the particle size of the liposome.

[0063] Example 8

[0064] A surface anesthetic consists of 4 mg of tetracaine hydrochloride, 4 mg of glycopyrrolate, 20 mg of a drug-encapsulating excipient and sucrose, wherein the final concentration of the sucrose is 5 mg / mL, and the drug-encapsulating excipient consists of 10 mg of cholesterol, 8 mg of soybean lecithin and 2 mg of DSPE-PEG.

[0065] The preparation method is the same as that in Example 4. The particle size is measured after collecting the atomized liquid. The particle size distribution after atomization is as follows: Figure 8 It shows that the particle size of the liposome prepared by the present invention is about 160nm, the PDI is 0.231, the particle size distribution is uniform, and the liposomes added with the taste masking agent sucrose still maintain a good particle size and particle size distribution after atomization.

[0066] Example 9

[0067] Take 2 mL of the surface anesthetic (liposome, recorded as mucosal adhesive sustained-release liposome) prepared in Example 6, place it in a dialysis bag with a molecular weight cutoff of 7K, and place it in 200 mL of PBS buffer solution, and heat and stir the liquid in the beaker in a 37°C water bath. Take 5 mL of the liquid in the beaker at 0.15 h, 0.5 h, 1 h, 2 h, 4 h, and 8 h, and use a UV spectrophotometer to detect the content of tetracaine. After each sampling, add 5 mL of PBS. A tetracaine hydrochloride solution with a concentration of 5 mg / mL was used as the control group. The results are as follows Fig. 9 It is shown that the liposome prepared by the present invention can slowly release tetracaine and continuously exert its effect at the drug action site.

[0068] Example 10

[0069] Experimental animals and groups:

[0070] 60 healthy adult male Wistar rats were selected, with a body weight of (210±10) g, and were placed in a quiet, warm (21-27°C), suitable humidity (45%-55%) environment, and caged, with 12 hours of light per day, free access to food and water, and the experiment was conducted after acclimating to the environment for 7 days. The experimental animals were divided into 3 groups by random grouping: a physiological saline group (N group, n=20), a 1% tetracaine group (T group, n=20), and an Example 8 topical anesthetic group (TG group, n=20). The difference between the 1% tetracaine group and Example 8 is that glycopyrrolate is not added, and the final concentration of tetracaine hydrochloride is 1%, and the rest is the same as Example 8.

[0071] Model building and material collection:

[0072] 1.1 Salivation experiment

[0073] Each group of rats was placed in a closed glass box, and oxygen was continuously inhaled to avoid rats from hypoxia and suffocation. The rats were placed in a quiet environment and waited for 30 minutes to avoid the experimental effect due to panic. The corresponding intervention measures were given to each group of rats, and the N group of rats was given atomization inhalation of normal saline; the T group was atomized by atomization inhalation of 1% tetracaine; the TG group was atomized by atomization inhalation of the surface anesthetic of Example 8, and each group of rats inhaled for 15 minutes. The rats were taken out and anesthetized by intraperitoneal injection of 2% pentobarbital 45mg / kg. After anesthesia, the rats of each group were fully fixed, and dry cotton balls (100mg) of similar weight were placed in the rat's mouth with hemostatic forceps, and the upper, lower, left and right were wiped once, and the interval was 3min. The mouth was wiped once again in the same way, and then the mass was weighed, and the mass of the cotton ball (100mg) was subtracted. The saliva weight of the rat within 10min was combined twice. Sampling was continued for 3 days (atomization inhalation was carried out every day in the 3 days of sampling) and the average was calculated as the final saliva weight of the rat. During the saliva collection process, the rat's head should be kept slightly lower to avoid suffocation. The weight of saliva collected from each group of rats was recorded.

[0074] 1.2 Tongue retraction test

[0075] After the rats in each group were anesthetized, the environment was kept quiet, and the anesthetized rats were taken out and placed on the upper and lower jaw support pad of the rat. The upper holes of the elastic support for the upper and lower jaws of the rat were put on the upper teeth of the rat and gently stretched upward. When the rat's mouth was fully exposed, the lower holes of the elastic support for the upper and lower jaws of the rat were quickly put on the mandibular teeth of the rat. At this time, due to the elastic effect of the support, the upper and lower jaws of the rat were stretched and the mouth was fully exposed. The elastic support was quickly fixed on the fixed column to ensure that the distance between the tongue surface of each rat and the microscope objective lens was consistent. At this time, the rat lay on its back on the pad, opened its mouth, and was at a 45° angle upward. Most rat tongues will automatically extend. For those who are not good at stretching, the inner core of a 1ml disposable syringe can be used to gently adjust it. Move the entire device to the same position under the microscope so that the rat tongue surface is facing the objective lens. Adjustment of the angle between the central axis of the tongue surface and the direction of light: The light enters from the right side of the tip of the rat tongue, and the light is at a 45° angle to the central axis of the rat tongue surface. After the first saliva collection, the central part of the rat tongue was stimulated with a 25G needle. The operation should be gentle to avoid excessive stimulation that may damage the rat tongue and cause discomfort, which may affect the subsequent experimental results. The tongue retraction time and tongue retraction strength of each group of rats were observed and recorded under a microscope. The tongue retraction strength was the proportion of the tongue retraction length observed under a microscope. The test was performed three times with an interval of 1 min, and the average was taken as the final result. The tongue retraction reaction time was calculated in S, and the tongue retraction strength was calculated in %.

[0076] Statistical analysis:

[0077] SPSS20.0 statistical software was used for analysis. The data were expressed as mean±standard deviation (x±s). The saliva weight, tongue retraction reaction time and tongue retraction intensity of rats in each group were compared by one-way analysis of variance. P<0.05 was considered statistically significant.

[0078] Experimental results:

[0079] 1.1 Saliva weight (mg)

[0080] Compared with the N and T groups, the saliva secretion weight of the rats in the TG group was significantly reduced (p < 0.05), while there was no statistical difference in the saliva secretion weight of the rats in the N and T groups (p > 0.05), see Table 1.

[0081] 1.2 Tongue retraction time (S) and tongue retraction intensity (%)

[0082] Compared with group N, the tongue retraction reaction time of rats in groups T and TG was significantly prolonged, and the tongue retraction intensity was significantly reduced (p < 0.05). There was no statistically significant difference in tongue retraction reaction time and tongue retraction intensity between rats in group T and group TG (p > 0.05), as shown in Table 1.

[0083] Table 1 Comparison of saliva quality, tongue retraction reaction time and tongue retraction intensity in different groups (x±s, n=20)

[0084] Group Saliva weight (mg) Tongue withdrawal reaction time (S) Tongue retraction strength (%) N Group 112.32±2.4 1.0±2.5 61.9±1.5 T Group <![CDATA[111.43±1.8 a ]]> <![CDATA[3.2±1.3 c ]]> <![CDATA[38.3±1.6 c ]]> TG group <![CDATA[91.25±3.1 b ]]> <![CDATA[2.8±1.2 d ]]> <![CDATA[40.2±3.1 d ]]>

[0085] Note: The letters in Table 1 indicate significant differences compared with group N, p < 0.05.

[0086] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A topical anesthetic, characterized in that: The topical anesthetic comprises tetracaine hydrochloride, glycopyrrolate and auxiliary materials, and the auxiliary materials comprise drug-carrying auxiliary materials.

2. The topical anesthetic according to claim 1, characterized in that The mass ratio of tetracaine hydrochloride, glycopyrrolate and drug encapsulating excipients is (3-5):(3-30):(25-55).

3. The topical anesthetic according to claim 1, characterized in that The drug encapsulating auxiliary materials include phospholipids, cholesterol and amphipathic lipids.

4. The topical anesthetic according to claim 3, characterized in that The mass ratio of phospholipids, cholesterol and amphiphilic lipids is (20-70):(20-60):(1-5).

5. The topical anesthetic according to claim 3, characterized in that The phospholipid includes at least one of soybean lecithin, lecithin, hydrogenated soybean lecithin, egg yolk lecithin, DLPC, DEPC, DPPS, DOPE, EPG, DPPG, DOPC, DPPC, DMPC and POPC.

6. The topical anesthetic according to claim 3, characterized in that The amphiphilic lipid includes at least one of PEG-DMG, PEG2000-c-DMG, PEG-c-DMA, DSPE-PEG, PEG-PE, Tween-20, Tween-80, DAA and PEG-c-DOMG.

7. The topical anesthetic according to claim 1, characterized in that The auxiliary materials also include taste-improving auxiliary materials, and the taste-improving auxiliary materials include at least one of sorbitol, menthol, sucrose, mannose, glucose, sucralose, citric acid, sodium chloride, sodium carbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate.

8. The topical anesthetic according to claim 7, characterized in that The final concentration of the taste improving auxiliary material is 5 mg / mL.

9. The topical anesthetic according to claim 1, characterized in that The dosage form of the topical anesthetic is a spray preparation.

10. The method for preparing the topical anesthetic according to any one of claims 1 to 9, characterized in that: The preparation method comprises a microfluidic method, a high-pressure homogenization method or a microfluidic method; the microfluidic method comprises the following steps: dissolving tetracaine hydrochloride, glycopyrrolate and a drug-encapsulating auxiliary material in anhydrous ethanol to obtain an ethanol phase, using a microfluidic device, setting the ethanol phase flow rate to 3 mL / min, and the purified water flow rate to 9 mL / min for mixing, and using purified water for dialyzing to remove ethanol to obtain a topical anesthetic.

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