Method for preparing transdermal microneedle based on gallium-based liquid metal

Abstract

The invention discloses a method for preparing a transdermal microneedle based on gallium-based liquid metal, which comprises the following steps: (1) heating the gallium-based liquid metal at a temperature higher than the melting point of the liquid metal, so that the gallium-based liquid metal is completely molten into a liquid state; (2) sucking the liquid metal preheated in the step (1) by using a microsyringe or a pipettor, and quickly injecting the liquid metal into a microneedle mold, so that the liquid metal is spread and completely covers a cavity of a needle tip in the mold; (3) transferring the mold in the step (2) into a constant-temperature vacuum box, and decompressing and degassing under vacuum; in the degassing process, the degassing temperature enables the liquid metal to be kept in a flowing liquid state all the time, and vacuumizing is conducted till the pressure is not higher than 10 Pa; the degassing time is not less than 5 hours; (4) continuously injecting the preheated gallium-based liquid metal or a degradable polymer solution into the mold to form a substrate of the microneedle; and (5) transferring the mold in the step (4) to a temperature far lower than the melting point of the liquid metal, and freezing and forming to obtain the transdermal microneedle.

Description

Technical Field

[0001] The invention relates to a method for preparing transdermal microneedles based on gallium-based liquid metal. Background Art

[0002] Microneedles are needles with micrometer-scale tips, generally 10 to 2000 μm in height and 10 to 50 μm in width, which can directly penetrate the epidermis to reach the skin tissue without causing pain. About half a century ago, Gerstel and Place first used microneedles in drug delivery systems, laying the foundation for the application of microneedles in transdermal drug delivery systems. In recent years, soluble polymer microneedles have attracted much attention due to their good biocompatibility, degradability, and controlled release of drug loads, and have been used in the study of drug, gene, protein, RNA, and vaccine delivery.

[0003] However, as a new transdermal drug delivery system, the existing soluble polymer microneedles have many advantages over traditional drug delivery methods, but they generally have problems such as poor tip strength and low drug loading, that is, the existing soluble polymer microneedles have problems such as poor tip strength and low drug loading. Gallium-based liquid metal has good biocompatibility and exists in a flowing liquid form in a temperature range close to human body temperature. It has shown application prospects in many biomedical fields such as flexible sensing, CT angiography, neural connection and repair, tumor treatment, and bone cement filling. Summary of the invention

[0004] Purpose of the invention: The purpose of the present invention is to provide a method for preparing transdermal microneedles based on gallium-based liquid metal. The microneedles prepared by this method are made of gallium-based liquid metal as the needle tip of the microneedle. The needle tip is solid at room temperature (25-30°C) and has good metal mechanical properties. At the same time, it is in a flowing liquid state within a temperature range close to human body temperature (about 37°C). Therefore, when the needle tip is injected into the human body, it can become a flowing state.

[0005] Technical solution: The method for preparing transdermal microneedles based on gallium-based liquid metal of the present invention comprises the following steps:

[0006] (1) heating the gallium-based liquid metal at a temperature higher than the melting point of the liquid metal to completely melt it into a liquid state;

[0007] (2) using a microsyringe or a pipette to absorb the liquid metal preheated in step (1), and quickly injecting it into the microneedle mold so that the liquid metal spreads and completely covers the cavity of the needle tip in the mold;

[0008] (3) transferring the mold of step (2) to a constant temperature vacuum box and degassing under vacuum; during the degassing process, the degassing temperature keeps the liquid metal in a flowing liquid state, and the vacuum is evacuated to no more than 10Pa; the degassing time is no less than 5 hours;

[0009] (4) Continuously inject the preheated gallium-based liquid metal or the degradable polymer solution into the mold to form the base of the microneedles.

[0010] (5) Transfer the mold in step (4) to a temperature far below the melting point of the liquid metal for freeze forming to obtain the transdermal microneedles.

[0011] The method for preparing transdermal microneedles based on gallium-based liquid metal according to the present invention comprises the following steps:

[0012] (1) Heat the gallium-based liquid metal at a temperature higher than the melting point of the liquid metal until it is completely melted into a liquid state.

[0013] (2) Use a micro syringe or pipette to suck up the preheated liquid metal in step (1), and quickly inject it into the microneedle mold, so that the liquid metal spreads and completely covers the cavity of the needle tip in the mold; inject the drug powder into the liquid metal, and slowly stir it with a syringe needle to make the drug powder evenly distributed in the liquid metal.

[0014] (3) Transfer the mold in step (2) to a constant-temperature vacuum chamber for vacuum degassing; during the degassing process, the degassing temperature keeps the liquid metal in a flowing liquid state all the time, evacuate to no higher than 10 Pa; the degassing time is no less than 5 hours.

[0015] (4) Continuously inject the preheated gallium-based liquid metal or the degradable polymer solution into the mold to form the base of the microneedles.

[0016] (5) Transfer the mold in step (4) to a temperature far below the melting point of the liquid metal for freeze forming to obtain the transdermal microneedles.

[0017] Among them, in step (1), the gallium-based liquid metal is pure gallium, eutectic gallium-indium alloy or eutectic gallium-indium-tin alloy, all of which are purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0018] Among them, in step (1), the water bath heating temperature is 14 - 30 °C higher than the melting point temperature of the liquid metal; the heating duration is 0.5 - 1 hour.

[0019] Among them, in step (2), after the liquid metal is filled, it is just slightly higher than the root of the cavity of the needle tip in the mold.

[0020] Among them, in step (2), the shape of the needle tip of the microneedle mold is a quadrangular pyramid, a cone or a triangular prism, and the density of the needle tip array on the microneedle mold is 100 - 400 needles per square centimeter.

[0021] Among them, in step (2), the mass-volume ratio of the liquid metal to the drug powder is: for 1 mL of liquid metal, 1 mg of drug powder is added.

[0022] Among them, the filled drug powder is a drug with a particle size less than 10 μm or a micro-nano material with a therapeutic effect.

[0023] Among them, in step (3), during the degassing process, the degassing temperature is the same as the heating temperature in step (1), and the degassing temperature is 14 - 30 °C higher than the melting point temperature of the liquid metal.

[0024] Among them, in step (4), the degradable polymer is hyaluronic acid, sodium hyaluronate, polyvinylpyrrolidone, chitosan, polyvinyl alcohol, polylactic acid or gelatin.

[0025] Among them, the freezing and forming temperature is -50 °C to 0 °C, and the freezing time is 4 - 6 hours.

[0026] Gallium-based liquid metal has good fluidity at room temperature. After melting the gallium-based liquid metal at an appropriate temperature, it is filled into a microneedle mold alone or together with drug powder (to prepare gallium-based microneedles or gallium-based microneedles carrying drugs based on different application scenarios). Through decompression and vacuum degassing, the air enclosed by the liquid metal at the tip of the needle tip spontaneously escapes through the liquid metal under the action of negative pressure, so as to achieve the purpose of discharging the air at the needle tip and making the gallium-based liquid metal fill the tip of the needle tip. Lower the temperature to a certain temperature below the melting point of the used gallium-based liquid metal. Under supercooling conditions, the gallium-based liquid metal can be solidified and formed. A thin layer of liquid metal or a solution of a degradable polymer can be continuously added at the root position of the needle tip cavity in the mold. After freeze-drying, a rigid all-metal microneedle with a liquid metal substrate or a flexible and bendable microneedle with a liquid metal tip and a polymer substrate is obtained; the microneedles prepared by the present invention need to be stored at a temperature below the melting point of the gallium-based liquid metal at the needle tip after demolding.

[0027] Beneficial effects: Compared with the prior art, the present invention has the following remarkable effects: The microneedles prepared by the method of the present invention use gallium-based liquid metal to make the tip of the microneedle. The tip is in a solid state at room temperature (25 - 30 °C) and has good metal mechanical properties. Compared with polymer microneedles, the mechanical properties of the microneedles can be significantly improved, making transdermal penetration easier. In addition, it can also effectively increase the drug loading capacity of the microneedles when loading drugs (the tip strength will not decrease significantly due to the increase in drug loading capacity). Since it is in a flowing liquid state within a temperature range close to the human body temperature, when its tip is injected into the human body, the drugs loaded therein can be fully released. When the prepared gallium-based microneedles do not carry drugs, when their tips are injected into the human body, they can become a flowing state and be used for photoacoustic imaging. Description of the Drawings

[0028] Figure 1Appearance photo of the pure gallium liquid metal microneedles prepared in Example 1;

[0029] Figure 2 SEM photo of the tip of the pure gallium liquid metal microneedles prepared in Example 1;

[0030] Figure 3 Compressive property curve graph of the pure gallium liquid metal microneedles prepared in Example 1;

[0031] Figure 4 Appearance photo of the eutectic gallium-indium liquid metal microneedles prepared in Example 2;

[0032] Figure 5 SEM photo of the tip of the eutectic gallium-indium liquid metal microneedles prepared in Example 2;

[0033] Figure 6 (a), Figure 6 (b) are respectively the optical microscope morphology diagrams of the tips of the pure gallium liquid metal microneedles prepared in Example 1 and Example 3;

[0034] Figure 7 Optical microscope photo of the tip of the pure gallium liquid metal microneedles prepared in Example 4;

[0035] Figure 8 Appearance photo of the liquid metal composite microneedles (Ga-SH MNs) on the flexible substrate prepared in Example 5;

[0036] Figure 9 Flexible display of the Ga-SH MNs substrate prepared in Example 5;

[0037] Figure 10 Compressive property curve graph of the Ga-SH MNs prepared in Example 5;

[0038] Figure 11 Cross-sectional SEM photo of the EGaIn-SH MNs prepared in Example 6;

[0039] Figure 12 (a), (b) are respectively the drug release curves of the all-gallium microneedles and the all-gallium-indium alloy microneedles in Example 7 and Example 8;

[0040] Figure 13 Morphology diagram of the tip of the pure gallium liquid metal microneedles prepared in Comparative Example 2;

[0041] Figure 14 Schematic diagram of the vacuum decompression degassing effect during the preparation process;

[0042] Figure 15 Morphology diagram of the tip of the pure gallium liquid metal microneedles prepared in Comparative Example 3;

[0043] Figure 16 This is the flowchart of the method of the present invention. Specific implementation mode

[0044] Example 1

[0045] A method for preparing transdermal microneedles based on gallium-based liquid metal without loading drugs, comprising the following steps:

[0046] (1) Weigh a small amount of pure gallium particles and melt them in a water bath at 50 °C for 0.5 hours;

[0047] (2) Then use a pipette to transfer 4 mL of molten liquid metal gallium and pour it into a microneedle mold (the microneedle mold uses a quadrangular pyramid-shaped tip, the tip height is 600 μm, and the root size of the tip is 320 μm × 320 μm), so that the liquid metal spreads and completely covers the cavity of the tip in the mold. Place the mold in a vacuum dryer and degas it under vacuum (pump to 10 Pa) at 40 °C for 5 hours;

[0048] (3) Continue to inject molten gallium liquid metal into the microneedle mold to make the substrate thickness 2000 μm, freeze it at -20 °C for 6 hours, and demold to obtain all-gallium liquid metal microneedles. Store it at a temperature (29.8 °C) below the melting point of the gallium-based liquid metal.

[0049] Figure 1 This is the appearance of the liquid metal microneedles with the tip and substrate all made of pure gallium prepared in Example 1. Figure 2 This is the scanning electron microscope picture of the tip part of the pure gallium microneedles prepared in Example 1. It can be Figure 1 seen that the tip of the pure gallium liquid metal microneedles prepared by vacuum degassing is completely formed and the substrate thickness is appropriate. Figure 2 It also confirms that the tip morphology of the pure gallium liquid metal microneedles is relatively complete, the shape is relatively sharp, and it has good puncture ability.

[0050] Figure 3 This is the compressive property curve of the pure gallium liquid metal microneedles prepared in Example 1. It can be Figure 3 seen that the force on the tip of the microneedle increases with the increase of the deformation of the tip, and there is no obvious fracture point. When the deformation of the tip is 0.1 mm, the total force on the microneedle is about 37 N, and the force on a single microneedle is about 0.164 N; when the deformation of the tip is 0.599 mm, the total force on the microneedle can reach 1058 N, and the force on a single microneedle is about 4.7 N, which far exceeds the force requirement for the microneedle to pierce the skin without breaking.

[0051] The transdermal microneedles prepared in Example 1 can transdermally transport liquid metal to the shallow surface layer of the skin. Combining with the excellent near-infrared photothermal conversion performance of the gallium-based liquid metal, it can locally heat the skin lesion site, thus realizing photothermal therapy.

[0052] Example 2

[0053] A method for preparing transdermal microneedles based on gallium-based liquid metal without loading drugs, comprising the following steps:

[0054] (1) Weigh a small amount of eutectic gallium-indium alloy and melt it in a water bath at 30 °C for 0.5 hours;

[0055] (2) Then use a pipette to transfer 4 mL of the melted eutectic gallium-indium alloy and pour it into a microneedle mold (the microneedle mold uses a quadrangular pyramid-shaped tip), so that the liquid metal spreads and completely covers the cavity of the tip in the mold. Place the mold in a vacuum dryer and degas it under vacuum (pump to 10 Pa) at 30 °C for 5 hours;

[0056] (3) Continue to inject the melted eutectic gallium-indium alloy into the microneedle mold to make the substrate thickness 2000 μm, freeze it at -30 °C for 6 hours, and demold to obtain all-gallium-indium alloy liquid metal microneedles; store them at a temperature (15.7 °C) below the melting point of the eutectic gallium-indium alloy.

[0057] Figure 4 Figure shows the microscopic photograph of the eutectic gallium-indium alloy microneedles prepared in Example 2, indicating a complete molding. Figure 5 Figure shows the SEM photograph of the tip of the eutectic gallium liquid metal microneedles prepared in Example 2. It can be seen that the tip is basically complete and sharp. However, due to its relatively low melting point, partial melting occurred during the test for some needles, resulting in a blunt tip for some of them.

[0058] Example 3

[0059] On the basis of Example 1, adjust the vacuum degassing process time to 2 hours, with other conditions remaining unchanged.

[0060] Figure 6 (a) shows the optical microscope morphology of the tip of the pure gallium liquid metal microneedles prepared in Example 1, Figure 6 (b) shows the optical microscope morphology of the tip of the pure gallium liquid metal microneedles prepared in Example 3. It can be seen that Figure 6 as can be seen,

[0061] the tip molding in Example 3 is incomplete and the tip bending is obvious, indicating that the vacuum degassing time in Example 3 is insufficient.

[0062] Example 4

[0063] On the basis of Example 1, adjust the freezing temperature after vacuum degassing to -50 °C, with other conditions remaining unchanged.

[0064] Figure 7Optical microscope photograph of the tip of the pure gallium liquid metal microneedle prepared in Example 4. When the freezing forming temperature is lower and the forming speed is faster, the pure gallium liquid metal microneedle prepared in Example 4 is basically the same as that in Example 1.

[0065] Example 5

[0066] A method for preparing flexible transdermal microneedles based on liquid metal gallium without loading drugs, comprising the following steps:

[0067] (1) Weigh a small amount of pure gallium particles and melt them in a water bath at 50 °C for 0.5 hours;

[0068] (2) Then use a pipette to transfer 4 mL of the melted liquid metal gallium and pour it into a microneedle mold (the microneedle mold uses a quadrangular pyramid tip), so that the liquid metal spreads and completely covers the tip cavity in the mold. Place the mold in a vacuum dryer and degas it under vacuum (pump to 10 Pa) at 40 °C for 5 hours;

[0069] (3) Inject a 10 wt% sodium hyaluronate (SH) solution with a mass concentration into the microneedle mold to make the substrate thickness 2000 μm; dry it at room temperature for 24 h (the purpose of drying at room temperature is to volatilize the water in SH and leave the SH matrix), then put it in a freezer at -20 °C for 6 hours and demold it to obtain a fully gallium tip liquid metal composite microneedle (Ga-SHMNs) with a flexible substrate. Store it at a temperature lower than the melting point of the gallium-based liquid metal (29.8 °C).

[0070] Figure 8 Photograph of the appearance of the Ga-SH composite microneedle. It can be seen that the tip of the microneedle is basically intact and sharp, and there is still a small amount of liquid metal film in the edge area. This is because it is difficult to completely remove the excess liquid metal when sucking it out. This film is also beneficial to the adhesion between the liquid metal gallium and the sodium hyaluronate substrate. Figure 9 Shows the flexible characteristics of the flexible substrate metal microneedle (Ga-SH MNs).

[0071] Figure 10 Is the compressive property curve graph of the Ga-SH MNs prepared in Example 5. From Figure 10 It can be seen that the force on the tip of the microneedle increases with the increase of the deformation of the tip, and there is no obvious fracture point. When the deformation of the tip is 0.4 mm, the total force on the microneedle is about 42 N, and the force on a single microneedle is about 0.187 N; when the deformation of the tip is 0.6 mm, the total force on the microneedle can reach 240.3 N, and the force on a single microneedle is about 1.068 N, which exceeds the force requirement for the microneedle to pierce the skin without breaking.

[0072] Example 6

[0073] A method for preparing flexible transdermal microneedles based on gallium-indium alloy without loading drugs, comprising the following steps:

[0074] (1) Weigh a small amount of eutectic gallium-indium alloy and melt it in a water bath at 30 °C for 0.5 hour;

[0075] (2) Then use a pipette to transfer 4 mL of the melted eutectic gallium-indium alloy, pour it into a microneedle mold (the microneedle mold uses a quadrangular pyramid-shaped tip), and make the liquid metal spread and completely cover the tip cavity in the mold. Place the mold in a vacuum dryer and degas it under vacuum (pump to 10 Pa) at 40 °C for 5 hours;

[0076] (3) Inject a 10 wt% sodium hyaluronate (SH) solution with a mass concentration into the microneedle mold to make the substrate thickness 2000 μm, dry it at room temperature for 24 h, then put it in a freezer at -20 °C for 6 hours and demold it to obtain a liquid metal composite microneedle with a flexible substrate (EGaIn-SH MNs); store it at a temperature (15.7 °C) below the melting point of the eutectic gallium-indium alloy.

[0077] Figure 11 SEM cross-sectional morphology photo of the EGaIn-SH composite microneedle prepared in Example 6. It can be seen that the tip and the substrate have obvious stratification and are tightly combined. This is because the carboxyl group (-COOH) in SH forms a coordination bond with Ga3+ on the liquid metal surface, enhancing the interfacial bonding strength, which greatly enhances the flexibility of the liquid metal microneedle.

[0078] Example 7

[0079] A method for preparing transdermal microneedles based on liquid metal gallium with drugs loaded according to the present invention, comprising the following steps:

[0080] (1) Weigh a small amount of pure gallium particles and melt them in a water bath at 50 °C for 0.5 hour;

[0081] (2) Then use a pipette to transfer 2 mL of the melted liquid metal gallium, pour it into a microneedle mold (the microneedle mold uses a quadrangular pyramid-shaped tip), inject 4 mg of drug powder (DOX) into the liquid metal, gently stir it with a syringe needle for 5 - 10 minutes after injection, then add 2 mL of the melted liquid metal gallium to it and stir again for 5 - 10 minutes; place the mold in a vacuum dryer and degas it under vacuum (pump to 10 Pa) at 40 °C for 5 hours;

[0082] (3) Continuously inject the melted gallium liquid metal into the microneedle mold to make the substrate thickness 2000 μm, freeze it at -20 °C for 6 hours, and demold to obtain Ga / DOX MNs.

[0083] The prepared liquid metal microneedles loaded with doxorubicin were placed in a constant temperature PBS solution at 37 °C, and the absorbance (Abs) corresponding to the wavelength of the ultraviolet-visible absorption peak of DOX in the solution (480 nm) was measured at regular intervals. Figure 12 (a) shows the drug release curve of Ga / DOX MNs in Example 7. The drug release of Ga / DOX MNs was rapid within 0 - 10 minutes, while the release rate gradually slowed down after 15 minutes, and finally the curve became stable after 80 minutes, and DOX was almost completely released into the solution.

[0084] In addition, the force on the tip of the Ga / DOX MNs prepared in Example 7 increased with the increase in the deformation of the tip, and no obvious break point occurred. When the deformation of the tip was 0.1 mm, the total force on the microneedles was about 3.1 N, and the force on a single microneedle was about 0.164 N; when the deformation of the tip was 0.599 mm, the total force on the microneedles could reach 1058 N, and the force on a single microneedle was about 4.7 N, which far exceeded the force requirement for the microneedles to pierce the skin without breaking.

[0085] Example 8

[0086] The method for preparing transdermal microneedles loaded with drugs based on gallium-indium alloy of the present invention includes the following steps:

[0087] (1) Weigh a small amount of eutectic gallium-indium alloy and melt it in a water bath at 30 °C for 0.5 hours;

[0088] (2) Then use a pipette to transfer 2 mL of the melted eutectic gallium-indium alloy, pour it into a microneedle mold (the microneedle mold uses a quadrangular pyramid tip), inject 4 mg of drug powder (DOX) into the liquid metal, gently stir for 5 - 10 minutes after injection, then add 2 mL of the melted eutectic gallium-indium alloy and stir again for 5 - 10 minutes; place the mold in a vacuum dryer and degas it under vacuum (pump down to 10 Pa) at 40 °C for 5 hours;

[0089] (3) Continue to inject the melted eutectic gallium-indium alloy into the microneedle mold to make the substrate thickness 2000 μm, freeze it at -30 °C for 6 hours, and demold to obtain EGaIn / DOX MNs.

[0090] The prepared liquid metal microneedles loaded with doxorubicin were placed in a constant temperature PBS solution at 37 °C, and the absorbance (Abs) corresponding to the wavelength of the ultraviolet-visible absorption peak of DOX in the solution (480 nm) was measured at regular intervals. Figure 12 (b) shows the release curve of EGaIn / DOX MNs in Example 8. The release curve of the all-gallium-indium alloy microneedles rose rapidly within 0 - 5 minutes, and the drug was almost completely released within 25 minutes.

[0091] The transdermal microneedles prepared in Examples 7-8 can be used for drug-loaded transdermal precise drug delivery, increasing the drug loading capacity of traditional soluble polymer microneedles and enhancing the mechanical properties of the microneedles at the same time.

[0092] Comparative Example 1

[0093] The method of Comparative Example 1 is the same as that of Example 1, and the only difference is that: in step (2) of Comparative Example 1, the temperature of vacuum decompression degassing is 15°C.

[0094] The pure gallium liquid metal microneedles could not be successfully prepared in Comparative Example 1. The melting point of gallium is about 29.8°C. When the ambient temperature is 15°C, pure gallium is in a solid state and has almost no fluidity. When negative pressure defoaming is carried out, the gallium and gallium oxide film on the surface will quickly solidify, resulting in the inability to discharge the gas at the tip of the needle. The gallium has solidified during vacuum pumping, and finally the forming fails. This shows that the ambient temperature must be higher than the melting point temperature of gallium during negative pressure defoaming, which is beneficial to the complete forming of pure gallium microneedles.

[0095] Comparative Example 2

[0096] The method of Comparative Example 2 is the same as that of Example 1, and the only difference is that: in step (2) of Comparative Example 2, the operation of vacuum decompression degassing is not carried out.

[0097] Figure 13 Figure shows the appearance photo of the tip of the pure gallium liquid metal microneedles prepared in Comparative Example 2. Through Figure 13 It can be seen that the pure gallium liquid metal microneedles prepared in Comparative Example 2 have incomplete forming without the degassing step, the tip is not sharp enough, and there are many cases of bending and missing of the needle tip. It shows that the air contained in the tip of the die needle will affect the complete filling of the liquid metal.

[0098] Figure 14 Figure shows the schematic diagram of vacuum decompression degassing during the preparation of pure gallium liquid metal microneedles. From Figure 14 it can be known that when liquid metal gallium and the microneedle die are placed in a negative pressure environment, due to the air pressure difference between the tip of the needle in the die and the outside, the air bubbles in the tip of the needle will continuously rise upward, leaving space for the liquid metal to flow into the tip of the needle, so as to realize the complete filling of the liquid metal tip of the needle.

[0099] Comparative Example 3

[0100] The method of Comparative Example 3 is the same as that of Example 1, and the only difference is that: in step (2) of Comparative Example 3, the vacuum decompression device is replaced, and a small vacuum pump is used to pump vacuum to 1000 Pa.

[0101] Figure 15 Figure shows the appearance photo of the tip of the pure gallium liquid metal microneedles prepared in Comparative Example 3. Through Figure 15It can be seen that the vacuum reduction of the pure gallium liquid metal microneedles prepared in Comparative Example 3 is insufficient, the forming is incomplete, and the tip is not sharp enough.

Claims

1. A method for preparing transdermal microneedles based on gallium-based liquid metal, characterized in that, It includes the following steps: (1) Heat the gallium-based liquid metal at a temperature higher than the melting point of the liquid metal until it is completely melted into a liquid state; (2) Use a micro syringe or pipette to suck up the preheated liquid metal in step (1), and quickly inject it into the microneedle mold, so that the liquid metal spreads and completely covers the cavity of the needle tip in the mold; (3) Transfer the mold in step (2) to a constant-temperature vacuum chamber for vacuum degassing; during the degassing process, the degassing temperature keeps the liquid metal in a flowing liquid state all the time, evacuate to no higher than 10 Pa; the degassing time is no less than 5 hours; (4) Continue to inject the preheated gallium-based liquid metal or an injectable biodegradable polymer solution into the mold to form the base of the microneedle; (5) Transfer the mold in step (4) to a temperature far lower than the melting point of the liquid metal for freeze molding to obtain the transdermal microneedle.

2. A method for preparing transdermal microneedles based on gallium-based liquid metal, characterized in that, It includes the following steps: (1) Heat the gallium-based liquid metal at a temperature higher than the melting point of the liquid metal until it is completely melted into a liquid state; (2) Use a micro syringe or pipette to suck up the preheated liquid metal in step (1), and quickly inject it into the microneedle mold, so that the liquid metal spreads and completely covers the cavity of the needle tip in the mold; inject the drug powder into the liquid metal, and slowly stir with a syringe needle to make the drug powder and the liquid metal mix evenly; (3) Transfer the mold in step (2) to a constant-temperature vacuum chamber for vacuum degassing; during the degassing process, the degassing temperature keeps the liquid metal in a flowing liquid state all the time, evacuate to no higher than 10 Pa; the degassing time is no less than 5 hours; (4) Continue to inject the preheated gallium-based liquid metal or an injectable biodegradable polymer solution into the mold to form the base of the microneedle; (5) Transfer the mold in step (4) to a temperature far lower than the melting point of the liquid metal for freeze molding to obtain the transdermal microneedle.

3. The method according to claim 1 or 2, characterized in that: In step (1), the gallium-based liquid metal is pure gallium, eutectic gallium-indium alloy or eutectic gallium-indium-tin alloy.

4. The method according to claim 1 or 2, characterized in that: In step (1), the water bath heating temperature is 14 - 30 °C higher than the melting point temperature of the liquid metal; the heating duration is 0.5 - 1 hour.

5. The method according to claim 1 or 2, characterized in that: In step (2), after the liquid metal is filled, it is just slightly higher than the root of the cavity of the needle tip in the mold.

6. The method according to claim 2, wherein: In step (2), the mass-volume ratio of the liquid metal to the drug powder mixture is: for 1 mL of liquid metal, add 1 mg of drug powder.

7. The method according to claim 6, characterized in that: The filled drug powder is a drug with a particle size less than 10 μm or a micro-nano material with a therapeutic effect.

8. The method according to claim 1 or 2, characterized in that: In step (3), during the degassing process, the degassing temperature is the same as the heating temperature in step (1), and the degassing temperature is 14 - 30 °C higher than the melting point temperature of the liquid metal.

9. The method according to claim 1 or 2, characterized in that: In step (4), the biodegradable polymer is hyaluronic acid, sodium hyaluronate, polyvinylpyrrolidone, chitosan, polyvinyl alcohol, polylactic acid or gelatin.

10. The method according to claim 1 or 2, characterized in that: In step (5), the freeze molding temperature is -50 °C to 0 °C, and the freezing time is 4 - 6 hours.

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