Anesthesia sustained-release microneedle and preparation method thereof

Abstract

In view of the problem that the drug release rate of existing anesthetic microneedles cannot be controlled and the mechanical strength of anesthetic microneedles is poor, the present invention provides an anesthetic sustained-release microneedle on the one hand, wherein the microneedle includes a molded preparation and a drug, wherein the drug includes an anesthetic drug and a metabolic agent for removing the anesthetic drug; the surfaces of the anesthetic drug and the metabolic agent are coated with a sustained-release barrier layer to form a corresponding vesicle structure, and the hydrophilicity of the sustained-release barrier layer on the surface of the anesthetic drug is greater than the hydrophilicity of the sustained-release barrier layer on the surface of the metabolic agent; the sustained-release barrier layer is a copolymer of polylactic acid and starch. On the other hand, the present invention also provides a method for preparing the above-mentioned microneedle array, comprising the following steps: the molded preparation and the drug are mixed in proportion and then injected into multiple microneedle molding areas on the mold, dehydrated at a temperature of 5 to 35°C to a water content of 3 to 15%, and the anesthetic sustained-release microneedle is obtained after demolding.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedles, and in particular relates to an anesthetic sustained-release microneedle and a preparation method thereof. Background Art

[0002] Local anesthesia acts as a local anesthetic by stabilizing the membrane potential of the nerve or reducing the membrane permeability to sodium ions, thereby blocking the conduction of nerve impulses. It is an anesthetic suitable for minor or local surgeries. Local anesthesia is usually administered by application or injection. The latter will cause obvious pain to the patient and affect patient compliance. At the same time, injection requires certain professional skills, which reduces the application scenarios of this administration method. Patients have a high degree of acceptance and cooperation when administering the drug by application, but its absorption time is about 1-5 hours, so it should be administered 30 minutes before surgery. The long waiting time for anesthesia limits its clinical application. In addition, the stratum corneum of the epidermis of the skin has a strong natural barrier effect, which will affect the absorption of drugs and reduce the permeability of anesthetics to a certain extent, resulting in only a small amount of drugs being absorbed and utilized by the capillaries in the dermis, affecting the analgesic effect of the drug.

[0003] Lidocaine hydrochloride is the most commonly used drug for local anesthesia. Its anesthetic principle is that after entering the tissue, it is neutralized by the weakly alkaline tissue fluid and is freed again in the form of bases to restore its lipid solubility. Only then can it penetrate the nerve sheath membrane and nerve membrane composed of lipid bilayers and enter the cell and bind to the inner mouth of the sodium channel to exert an anesthetic effect. In the prior art, lidocaine is prepared into microneedles for local anesthesia, such as the publication number CN111991344A, a microneedle patch suitable for local anesthesia and its preparation method, which is a soluble microneedle patch prepared by a water-soluble high molecular polymer. The needle body can encapsulate more local anesthetic drugs to meet the needs of longer anesthesia.

[0004] The current soluble anesthetic microneedles mainly have the following problems: 1. The problem of drug release rate. Due to the low drug loading of the microneedles, the drug is released quickly after dissolution and does not stay in the local tissue for a long time, which cannot ensure the long-lasting efficacy. Secondly, for local anesthetics, the released drugs must meet the working concentration of the drugs while avoiding systemic toxicity caused by the initial drug burst release. At the same time, studies have found that after surgery, patients cannot metabolize or excrete these drugs in time, which is prone to side effects and brings a large number of adverse reactions to patients taking anesthesia drugs, such as indigestion, chills, etc., causing secondary damage to the human body after surgery, affecting the body's postoperative immunity, and reducing the cure rate of the disease. Therefore, after the expected drug effect time ends, the anesthetic in the body must be metabolized as soon as possible to reduce drug side effects.

[0005] 2. The mechanical strength of microneedles. In order to ensure the efficacy of anesthetics, a large amount of anesthetics needs to be added to the soluble microneedles, which has a great impact on the mechanical strength of the microneedles, resulting in poor microneedle puncture or easy needle breakage. Therefore, how to improve the analgesic effect of drugs while ensuring the mechanical strength of soluble microneedles is an urgent problem to be solved in the industry. Summary of the invention

[0006] In view of the problems that the drug release rate of existing anesthetic microneedles cannot be controlled and the mechanical strength of anesthetic microneedles is poor, the present invention provides an anesthetic sustained-release microneedle.

[0007] The microneedle comprises a molded preparation and a drug, wherein the drug comprises an anesthetic drug and a metabolic agent for removing the anesthetic drug;

[0008] The surfaces of the anesthetic drug and the metabolic agent are both coated with a sustained-release barrier layer to form a corresponding vesicle structure, and the hydrophilicity of the sustained-release barrier layer on the surface of the anesthetic drug is greater than that of the sustained-release barrier layer on the surface of the metabolic agent;

[0009] The sustained-release barrier layer is a copolymer of polylactic acid and starch.

[0010] Optionally, the anesthetic drug is at least one amide anesthetic, specifically one or more of lidocaine hydrochloride, tetracaine, ropivacaine or brucaine.

[0011] Optionally, the anesthetic drug is lidocaine hydrochloride.

[0012] Optionally, the metabolic agent is isoproterenol.

[0013] Optionally, the mass ratio between the molded preparation and the drug is (28~113): (3~22).

[0014] Optionally, the molding formulation includes the following components by weight:

[0015] 4-9 parts of polyvinyl alcohol, 12-18 parts of polyvinyl pyrrolidone, and 2-5 parts of hydroxyethyl cellulose.

[0016] Optionally, the mass ratio of the anesthetic drug to the metabolic agent is (8~3):(3~1).

[0017] Optionally, the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drug is (4-9):(1-5), and the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the metabolic agent is (11-14):(1-2).

[0018] Optionally, the anesthetic drug is divided into three equal batches according to the mass ratios of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drug, which are 4:5, 4:3, and 4:1 respectively.

[0019] The present invention also provides a method for preparing the above-mentioned anesthetic sustained-release microneedle, comprising the following steps:

[0020] The molding preparation and the drug are mixed in proportion and injected into the multiple microneedle molding areas on the mold, dehydrated at a temperature of 5-35° C. to a water content of 3-15%, and the anesthetic sustained-release microneedles are obtained after demolding.

[0021] Beneficial effects of the present invention:

[0022] In order to control the dissolution and release rate of the microneedle after entering the tissue, the present invention wraps one or more layers of sustained-release barrier layer on the surface of the anesthetic drug. The sustained-release barrier layer is formed by melt polymerization of polylactic acid and starch according to a certain mass ratio, and plays a sustained-release role in the body. At the same time, the hydrophilicity of the sustained-release barrier layer can be changed by adjusting the mass ratio of polylactic acid and starch. The more starch accounts for, the stronger the hydrophilicity of the sustained-release barrier layer, and vice versa. The present invention divides the anesthetic drug into three batches according to different mass ratios of polylactic acid and starch, which can achieve the effect of anesthetic drug release in batches; after the anesthetic drug is released and the desired anesthesia time is reached, it is necessary to further remove the anesthetic drug remaining in the body to reduce the toxic and side effects of the drug. The present invention uses isoproterenol as an anesthetic drug metabolizer. Isoproterenol can increase liver blood flow and accelerate the metabolism of anesthetic drugs. The hydrophilicity of the sustained-release barrier layer on the surface of the metabolizer is much lower than that of the sustained-release barrier layer on the surface of the anesthetic drug, so it can be ensured that the metabolism of the drug residue is accelerated only after the anesthetic drug is released.

[0023] In order to solve the problem of reduced mechanical strength of microneedles after adding anesthetic drugs, the present invention uses specific weight portions of polyvinyl alcohol, polyvinyl pyrrolidone and hydroxyethyl cellulose, which are intertwined with each other to form a more stable supporting skeleton. Experiments have shown that good mechanical strength of microneedles can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is a plan view of a microneedle array according to Example 1 of the present invention;

[0025] Figure 2 is a schematic plan view of the parafilm membrane after being pierced by a microneedle in Example 4 of the present invention;

[0026] Figure 3A , 3B 3C and 3D are schematic diagrams of ink penetration of parafilm membranes of Examples 1 to 3 of the present invention and Comparative Example 1, respectively;

[0027] Figure 4 This is a field experiment picture of applying anesthetic microneedles on the back of mice in Example 5 of the present invention. Implementation

[0028] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] In the description of the present invention, it should be understood that the term "vesicle" refers to a hollow spherical structure that completely encapsulates a specific drug, thereby isolating the internal space of the vesicle from the external space; the term "sustained release" refers to the diffusion of the active ingredient from the biodegradable polymer and / or the release of the active ingredient due to swelling, dissolution or degradation of the biodegradable polymer over an extended period of time, such as at least two days, so that the active ingredient can be delivered throughout the entire period, thereby allowing less frequent administration.

[0030] In the description of the present invention, unless otherwise specified, "plurality" means two or more than two, "at least" and "at most" mean including the number, and "greater than" means not including the number.

[0031] Dissolvable microneedles

[0032] In one embodiment, the anesthetic microneedles are formed of a composition comprising a water-soluble shaped preparation of an anesthetic drug.

[0033] The water-soluble molding preparations include but are not limited to polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, sugar, acrylonitrile-butadiene-styrene copolymer (ABS), ethylene-vinyl acetate copolymer, polyvinylidene chloride, polyfluoroolefin, polyperfluoroolefin, polyacrylonitrile, polyvinyl ketone, dextran, cellulose, heparin, hyaluronic acid, alginate, etc.

[0034] In one embodiment, the water-soluble molding preparation includes the following weight components: 4-9 parts of polyvinyl alcohol, 12-18 parts of polyvinyl pyrrolidone, and 2-5 parts of hydroxyethyl cellulose, wherein the molecular weight of the polyvinyl pyrrolidone is 3500-150000, and the viscosity of the polyvinyl alcohol is 2.4-42.6mpas. The inventors have found through a large number of experiments that by combining the materials in the above weight ratio, polyvinyl alcohol and polyvinyl pyrrolidone are intertwined with each other, and the difference in the length of their molecular chains plays a complementary role. The molecular chains are intertwined to form a more stable support skeleton, thereby improving the overall strength of the microneedle.

[0035] Anesthetic drugs

[0036] In one embodiment, the anesthetic drug includes but is not limited to lidocaine hydrochloride, tetracaine, ropivacaine or brucaine, mepivacaine, pyrocaine and other amide local anesthetic drugs. Preferably, in one embodiment, the anesthetic drug can be lidocaine hydrochloride, which has stable performance, rapid onset of effect, and strong diffusion and penetration ability.

[0037] At the same time, in order to prolong the anesthesia time and reduce the side effects such as poisoning of lidocaine hydrochloride, in some embodiments, vasoconstrictors such as adrenaline can be added to lidocaine hydrochloride, and the dosage does not exceed 0.6 mg, which can cause local vasoconstriction, delay the absorption of local anesthetics, accelerate the onset time, enhance the blocking effect, prolong the action time, reduce the toxic reaction of local anesthetics, eliminate the vasodilation effect caused by local anesthetics, and reduce wound bleeding. In some embodiments, the pharmacodynamic function of lidocaine can be improved by mixing adrenaline with 0.33% lidocaine hydrochloride and 0.07% sodium bicarbonate solution at a ratio of 1:600000.

[0038] Slow-release barrier layer

[0039] In one embodiment, the sustained-release barrier layer is a copolymer formed by melt polymerization of polylactic acid and starch. In one embodiment, the thickness of the sustained-release barrier layer may be 10-100 nm, and preferably the thickness of the sustained-release barrier layer may be 50-80 nm; in one embodiment, the melt polymerization method is specifically as follows:

[0040] A certain amount of polylactic acid and starch were added to a flask, and the temperature was raised to 60°C under nitrogen protection. After they were completely dissolved, a certain amount of chloroform solution was added in batches. After the addition was completed, the reaction was continued for 4 hours to obtain a copolymer.

[0041] Polylactic acid has good biocompatibility and is easily biodegraded and absorbed. It is also a hydrophobic polymer that is not easily soluble in the body, so it can prevent drugs from being dissolved. At the same time, polylactic acid can change its hydrophilicity by copolymerizing with other monomers or oligomers, such as starch, dihydroxyethyl methacrylate (HEMA), N2 vinyl pyrrolidone (NVP), glycidyl methacrylate (GM), and trimethylsiloxane 2-methacrylate propoxysilane (TRIS).

[0042] In one embodiment, the starch is amylopectin, and the starch can be compounded with a hydrophilic colloid to enhance its hydrophilicity. In one embodiment, the hydrophilic colloid can be one or more of gum arabic, xanthan gum, guar gum, etc.

[0043] In one embodiment, the sustained-release barrier layer may further include ethyl dichlorophosphate. Ethyl dichlorophosphate has good biocompatibility and high structural variability, which is beneficial for structural modification or functionalization and can be used as a good combination material for polylactic acid and starch.

[0044] In one embodiment, in order to achieve the function of releasing the metabolic agent after the release of the anesthetic drug is completed, the hydrophilicity of the sustained-release barrier layer is changed by adjusting the mass ratio of polylactic acid and starch. The higher the proportion of starch, the stronger the hydrophilicity of the sustained-release barrier layer, and vice versa. Therefore, in this embodiment, the proportion of starch in the sustained-release barrier layer on the surface of the anesthetic drug is increased to be higher than the proportion of starch in the sustained-release barrier layer on the surface of the metabolic agent. Through such adjustment, the sustained-release barrier layer on the surface of the anesthetic drug can be dissolved before the metabolic agent, thereby releasing the anesthetic drug earlier.

[0045] At the same time, in order to control the release time point of the anesthetic drug and the metabolic agent, in one embodiment, the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drug is (4-9): (1-5), and the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the metabolic agent is (11-14): (1-2). Preferably, the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drug is 6:1, and the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the metabolic agent is 12:1. With such a ratio, the anesthetic drug can be maintained for a desired time after release and then cleared by releasing the metabolic agent.

[0046] Release in batches

[0047] In one embodiment, in order to avoid the systemic toxicity caused by the sudden release of anesthetic drugs in the body and take into account the rapid effectiveness of anesthetic drugs, the anesthetic drugs are divided into multiple batches according to the different mass ratios of polylactic acid and starch in the sustained-release barrier layer on the surface. In one embodiment, all batches are equal, and the amount of each batch can also be adjusted according to demand. In one embodiment, the anesthetic drugs are divided into three equal batches according to the mass ratios of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drugs, which are 4:5, 4:3, and 4:1, respectively, so as to achieve multiple release of drugs and avoid sudden release or uneven overall release rate of drugs.

[0048] Preparation method of microneedle array

[0049] An embodiment of the present invention provides a method for preparing a microneedle array, comprising the following steps:

[0050] Lidocaine hydrochloride is dissolved in water to prepare an aqueous solution, and then an organic solution containing polylactic acid and starch copolymer is mixed with the lidocaine hydrochloride aqueous solution in a mechanical turbulent manner, and then dispersed into a second aqueous phase to form solvent spheres, and finally the organic solvent is removed to obtain lidocaine hydrochloride vesicles. Isoproterenol vesicles are prepared in the same manner.

[0051] The prepared molding preparation and the drug prepared by mixing lidocaine hydrochloride vesicles and isoproterenol vesicles with water are mixed in a mass ratio of (28-113): (3-22) to form a microneedle molding liquid, and then injected into multiple microneedle molding areas on the mold. Preferably, the molding preparation and the drug are mixed in a mass ratio of (55-78): (14-20) to increase the drug loading of the microneedle while ensuring the basic mechanical strength of the microneedle. Dehydrate at a temperature of 5-35°C to a water content of 3-15%, and after demolding, the anesthetic sustained-release microneedle is obtained.

[0052] Providing a mold, wherein a plurality of microneedle forming areas are distributed on the mold, and a liquid injection port is provided on the surface of the microneedle forming area, and a microneedle forming liquid is filled into the needle-shaped cavity through the liquid injection port;

[0053] Drying and removing the solvent in the microneedle forming liquid, so that the microneedle forming liquid shrinks to the tip of the needle-shaped cavity and solidifies;

[0054] In one embodiment, a layered microneedle is prepared, a substrate forming liquid is filled into the needle-shaped cavity, and the substrate forming liquid is at least partially formed on the surface of the microneedle forming area, the substrate forming liquid is dried and solidified, and demolding is performed to obtain a substrate and a microneedle connected to the substrate.

[0055] The present invention is further described below by way of examples.

[0056] Example 1

[0057] Weigh 4 parts of polyvinyl alcohol (viscosity 2.8 mpas), 12 parts of polyvinyl pyrrolidone (molecular weight 210000), and 2 parts of hydroxyethyl cellulose by weight, add them into 15 parts of water, disperse them by heating at 90°C, and cool them down to obtain a molded preparation for use;

[0058] The lidocaine hydrochloride vesicles and isoproterenol vesicles were mixed in a mass ratio of 3:1 to obtain the drug, 50 mg of the drug and 1.5 g of the molding preparation were weighed, 10 ml of sterile water were added, and then centrifuged in a centrifuge for 1 min, then taken out and placed in a vortex mixer for mixing for 15 min, and finally centrifuged for 3 min to eliminate bubbles to obtain a microneedle molding solution.

[0059] The PET mesh is glued to the mold, and 60 μl of microneedle forming liquid is transferred to the circular hole on the mold with a pipette. After vacuuming with a vacuum pump for 15 minutes, the PET mesh is peeled off, and the excess microneedle forming liquid on the mold is scraped off with a scraper. The mold is placed in a drying oven for drying for 10 minutes, and then the base forming liquid is scraped onto the mold. After vacuuming for 20 minutes, the mold is air-dried. After drying, the mold is taken out, and the circular hole on the mold is covered with a basement membrane corresponding to the circular hole on the mold. Then, the membrane is peeled off to obtain anesthesia microneedles, as shown in FIG. Figure 1 shown.

[0060] Example 2

[0061] Weigh 5 parts of polyvinyl alcohol (viscosity 2.8 mpas), 15 parts of polyvinyl pyrrolidone (molecular weight 210000), and 3 parts of hydroxyethyl cellulose by weight, add them into 15 parts of water, disperse them by heating at 90°C, and cool them down to obtain a molded preparation for use;

[0062] The lidocaine hydrochloride vesicles and isoproterenol vesicles were mixed in a mass ratio of 3:1 to obtain the drug, 50 mg of the drug and 1.5 g of the molding preparation were weighed, 10 ml of sterile water were added, and then centrifuged in a centrifuge for 1 min, then taken out and placed in a vortex mixer for mixing for 15 min, and finally centrifuged for 3 min to eliminate bubbles to obtain a microneedle molding solution.

[0063] The PET mesh was glued to the mold, and 60 μl of microneedle forming liquid was transferred to the circular hole on the mold with a pipette. After vacuuming with a vacuum pump for 15 minutes, the PET mesh was peeled off, and the excess microneedle forming liquid on the mold was scraped off with a scraper. The mold was placed in a drying oven and dried for 10 minutes. The base forming liquid was then scraped onto the mold, and then vacuumed for 20 minutes and the mold was air-dried. After drying, the mold was taken out, and the circular hole on the mold was covered with a basement membrane corresponding to the circular hole on the mold. The film was then peeled off to obtain the anesthetic microneedle.

[0064] Example 3

[0065] Weigh 9 parts of polyvinyl alcohol (viscosity 2.8 mpas), 18 parts of polyvinyl pyrrolidone (molecular weight 210000), and 5 parts of hydroxyethyl cellulose by weight, add them into 15 parts of water, disperse them by heating at 90°C, and cool them down to obtain a molded preparation for use;

[0066] The lidocaine hydrochloride vesicles and isoproterenol vesicles were mixed in a mass ratio of 3:1 to obtain the drug, 50 mg of the drug and 1.5 g of the molding preparation were weighed, 10 ml of sterile water were added, and then centrifuged in a centrifuge for 1 min, then taken out and placed in a vortex mixer for mixing for 15 min, and finally centrifuged for 3 min to eliminate bubbles to obtain a microneedle molding solution.

[0067] The PET mesh was glued to the mold, and 60 μl of microneedle forming liquid was transferred to the circular hole on the mold with a pipette. After vacuuming with a vacuum pump for 15 minutes, the PET mesh was peeled off, and the excess microneedle forming liquid on the mold was scraped off with a scraper. The mold was placed in a drying oven and dried for 10 minutes. The base forming liquid was then scraped onto the mold, and then vacuumed for 20 minutes and the mold was air-dried. After drying, the mold was taken out, and the circular hole on the mold was covered with a basement membrane corresponding to the circular hole on the mold. The film was then peeled off to obtain the anesthetic microneedle.

[0068] Comparative Example 1

[0069] Weigh 5 parts of polyvinyl alcohol (viscosity 2.8 mpas), 14 parts of polyvinyl pyrrolidone (molecular weight 210000), and 3 parts of hydroxyethyl cellulose by weight, add them into 15 parts of water, disperse them by heating at 90°C, and cool them down to obtain a molded preparation for use;

[0070] The lidocaine hydrochloride vesicles and isoproterenol vesicles were mixed in a mass ratio of 3:1 to obtain the drug, 50 mg of the drug and 1.5 g of the molding preparation were weighed, 10 ml of sterile water were added, and then centrifuged in a centrifuge for 1 min, then taken out and placed in a vortex mixer for mixing for 15 min, and finally centrifuged for 3 min to eliminate bubbles to obtain a microneedle molding solution.

[0071] The PET mesh was glued to the mold, and 60 μl of microneedle forming liquid was transferred to the circular hole on the mold with a pipette. After vacuuming with a vacuum pump for 15 minutes, the PET mesh was peeled off, and the excess microneedle forming liquid on the mold was scraped off with a scraper. The mold was placed in a drying oven and dried for 10 minutes. The base forming liquid was then scraped onto the mold, and then vacuumed for 20 minutes and the mold was air-dried. After drying, the mold was taken out, and the circular hole on the mold was covered with a basement membrane corresponding to the circular hole on the mold. The film was then peeled off to obtain the anesthetic microneedle.

[0072] Example 4

[0073] Parafilm sealing film puncture experiment: The microneedle patches of Examples 1 to 3 and Comparative Example 1 were selected, and 5 layers of parafilm films were stacked. The microneedle patches were placed under a universal material testing machine with the needle tip facing the parafilm film. The microneedle was pressed with a force of 147N (approximately equal to the pressure of an adult's finger) to make the microneedle penetrate into the parafilm. The parafilm film after penetration was as shown in FIG. Figure 2 After the experiment, the parafilm membrane was taken out, and red ink was used to soak the parafilm membrane. By observing whether the red ink can penetrate the parafilm membrane, the number of parfilm membrane layers penetrated by the microneedle was determined.

[0074] The results obtained in Examples 1 to 3 are as follows Figure 3A , 3B, 3C, the results obtained in Comparative Example 1 are as follows Figure 3D shown.

[0075] The results show that after the microneedle patches of Examples 1 to 3 are punctured through the parafilm sealing film, the red ink can penetrate into the fifth layer, that is, it can be determined that the microneedle punctures the fifth layer of the parafilm film under 147N.

[0076] Comparative Example 1 can only penetrate the fourth layer and does not impregnate the fifth layer. It can be explained that the mechanical strength of the microneedle in Comparative Example 1 is significantly poor. It can be inferred that adjusting the dosage ratio between polyvinyl alcohol, polyvinyl pyrrolidone and hydroxyethyl cellulose has a significant effect on the mechanical strength of the microneedle. It is further inferred that the ratio adopted in the technical solution of the present invention can maximize the mechanical strength of the microneedle while ensuring the drug loading.

[0077] Example 5

[0078] Five C57BL / 6 male mice (6 weeks old, about 500 g) were selected for evaluation of drug anesthetic efficacy. The temperature of the enclosure environment was controlled at 18-23°C, and a 12-hour light / 12-hour dark diurnal cycle was maintained. After a 12-day environmental adaptation period, the C57BL / 6 male mice were randomly assigned to No. 1 to No. 5, and the backs of all mice were shaved. The anesthetic microneedles prepared in Examples 1-3 were attached to the backs of mice No. 1-3, respectively. Figure 4 As shown, the patch was removed after 20 minutes; the anesthetic microneedles prepared in Comparative Example 2 were pasted on the back of mouse No. 4. The method of Comparative Example 2 was basically the same as that of Example 1, except that lidocaine hydrochloride was not made into a vesicle structure in Comparative Example 2, but an aqueous solution of lidocaine hydrochloride was directly added, and no isoproterenol vesicles were contained; the anesthetic microneedles prepared in Comparative Example 3 were pasted on the back of mouse No. 5. The method of Comparative Example 3 was basically the same as that of Example 1, except that no isoproterenol vesicles were added to the drug in Comparative Example 3. The reaction of the patch site to acupuncture was tested at 0 minutes, 10 minutes, 1 hour, 6 hours, 10 hours, and 12 hours after the patch, and the blood of the mice was sampled in the corresponding time period, and the concentration of lidocaine hydrochloride in the blood was detected by high performance liquid chromatography. The following experimental results were obtained:

[0079] Table 1

[0080]

[0081] From the comparison in Table 1, it can be seen that the concentration of lidocaine hydrochloride in the blood of mice No. 1-3 and No. 5 decreases slowly over time, which is manifested in no obvious reaction in acupuncture reaction. There is no sudden release of the drug in the early stage of application, and after reaching the expected time (10h), the concentration of lidocaine hydrochloride in the blood drops sharply and is almost cleared; while the change of lidocaine hydrochloride in the blood of mouse No. 4 over time is greater than that of the above mice, and after 10h, it has dropped to a concentration value that cannot guarantee the efficacy, showing that the mouse has a strong reaction to acupuncture; and after 12h, there is still a large concentration of lidocaine hydrochloride residue in the blood of mouse No. 5. Through the above experiments, it can be inferred that lidocaine hydrochloride wrapped in a sustained-release barrier layer has a good sustained-release function, which greatly exceeds the 4-6h anesthesia time of general local anesthetics. At the same time, isoproterenol wrapped in a sustained-release barrier layer can achieve the function of rapid removal of drug residues after anesthesia.

[0082] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An anesthetic sustained-release microneedle, characterized in that: The microneedle comprises a molded preparation and a drug, wherein the drug comprises an anesthetic drug and a metabolic agent for removing the anesthetic drug; the surfaces of the anesthetic drug and the metabolic agent are both coated with a sustained-release barrier layer of the same thickness to form a corresponding vesicle structure, and the hydrophilicity of the sustained-release barrier layer on the surface of the anesthetic drug is greater than the hydrophilicity of the sustained-release barrier layer on the surface of the metabolic agent; the sustained-release barrier layer is a copolymer of polylactic acid and starch; The metabolic agent is isoproterenol; The molding preparation comprises the following components by weight: 4-9 parts of polyvinyl alcohol, 12-18 parts of polyvinyl pyrrolidone, and 2-5 parts of hydroxyethyl cellulose; The mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drug is (4-9):(1-5), and the mass ratio of polylactic acid and starch in the sustained-release barrier layer on the surface of the metabolic agent is (11-14):(1-2).

2. The anesthetic sustained-release microneedle according to claim 1, characterized in that: The anesthetic drug is at least one amide anesthetic, specifically one or more of lidocaine hydrochloride, tetracaine, ropivacaine or brucaine.

3. The anesthetic sustained-release microneedle according to claim 2, characterized in that: The anesthetic drug is lidocaine hydrochloride.

4. The anesthetic sustained-release microneedle according to claim 1, characterized in that: The mass ratio between the molded preparation and the drug is (28-113):(3-22).

5. The anesthetic sustained-release microneedle according to claim 1, characterized in that: The mass ratio of the anesthetic drug to the metabolic agent is (8-3):(3-1).

6. The anesthetic sustained-release microneedle according to claim 1, characterized in that: The anesthetic drug is divided into three batches of equal amounts according to the mass ratios of polylactic acid and starch in the sustained-release barrier layer on the surface of the anesthetic drug of 4:5, 4:3 and 4:1 respectively.

7. A method for preparing the anesthetic sustained-release microneedle according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: mixing the molding preparation and the drug in proportion and injecting the mixture into a plurality of microneedle molding areas on the mold, dehydrating the mixture at a temperature of 5-35° C. to a water content of 3-15%, and obtaining the anesthetic sustained-release microneedles after demoulding.

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