Gas-driven double-cavity microneedle as well as preparation method and application thereof

Abstract

The invention relates to a gas-driven double-cavity microneedle as well as a preparation method and application thereof. The preparation method comprises the following steps: S1, preparing a needle tip solution, filling a microneedle mold with the needle tip solution, vacuumizing and drying to obtain a blank cavity microneedle with a first-stage cavity and a second-stage cavity; s2, sequentially filling the I-stage cavity with medicine powder and filling the II-stage cavity with aerogenesis powder through a vacuum method or a centrifugal method, adhering and fixing a medical adhesive tape to the surface of the blank cavity microneedle, and demolding to obtain the gas-driven double-cavity microneedle, the invention also discloses application of the gas-driven double-cavity microneedle prepared by the method in preparation of a drug delivery system, a vaccine delivery system, a medical beauty product, a diagnosis monitoring marker and a gene therapy vector system. The invention has the effects of supporting orthogonal regulation and control of gas production kinetics and drug release behavior, being capable of carrying out customized compatibility aiming at different disease treatment scenes, and having broad-spectrum applicability and clinical transformation potential.

Description

Technical Field

[0001] The present invention relates to the technical field of microneedles, and in particular to a gas-driven double-lumen microneedle and a preparation method and application thereof. Background Art

[0002] Transdermal drug delivery systems (TDDS), a key branch of modern drug delivery technology, not only enhance drug bioavailability but also improve patient compliance and efficacy. Microneedles (MNs) consist of numerous microneedle tips connected to a base in an array. They offer significant advantages such as safety, efficiency, minimal invasiveness, and painlessness. Dissolvable MNs achieve transdermal drug delivery by dissolving the needle material in tissue fluid, significantly improving drug delivery safety and patient acceptance. They provide efficient delivery pathways for biomacromolecules, nanodrug carrier systems, and vaccine antigens, and exhibit significant industrial potential in cutting-edge fields such as targeted tumor therapy, gene vaccination, and chronic disease management. However, the drug release process of soluble MNs relies on the passive dissolution and diffusion of the matrix material, which poses challenges in regulating drug release kinetics and insufficient deep tissue penetration, potentially limiting the effectiveness of drug delivery. To enhance transdermal drug penetration, current research often incorporates adjunctive technologies such as iontophoresis or sonophoresis. While this improves therapeutic efficacy, it also increases treatment cost and operational complexity. Gas-driven microneedles, a typical representative of the third generation of smart microneedles, represent a trend away from single-purpose mechanical penetration toward multifunctionality. They significantly improve the efficiency and precision of drug delivery and have become a research focus in biomedical engineering. By generating gas, gas-driven microneedles achieve sustained drug release in the dermis and utilize the skin's rich capillary network to ensure stable drug delivery into the bloodstream.

[0003] Chinese patent publication number CN118873478A discloses a magnesium-containing soluble microneedle patch characterized by comprising a backing layer and a microneedle array disposed on the backing layer. The microneedles in the microneedle array have a two-stage structure, each comprising a tip and a tail. The tip is made of polyvinyl pyrrolidone, chondroitin sulfate, and a therapeutic drug, while the tail and backing layer are made of magnesium particles and polyvinyl pyrrolidone. Although the microneedles described above can generate gas, dissolving the gas-generating powder in dimethyl sulfoxide presents significant biosafety concerns. Due to the high boiling point of dimethyl sulfoxide (189°C), it is difficult for the gas-generating powder to completely evaporate during the microneedle curing process, which may lead to biotoxicity or irritation risks, especially for sensitive skin or medical applications.

[0004] The Chinese patent with the authorization announcement number CN119074636B discloses a rapid separation microneedle patch, which includes a needle tip prepared from a needle tip liquid and a separation backing prepared from a separation base liquid; the needle tip liquid is composed of a drug-containing inclusion compound solution, a photoinitiator, and a hypotonic agent in a volume-mass ratio of 1 mL: 0.005-0.01 g: 0.05-0.1 g; the concentration of the drug-containing inclusion compound in the drug-containing inclusion compound solution is 0.25 g / mL-0.75 g / mL, and the drug-containing inclusion compound is prepared by first covalently linking a β-cyclodextrin conjugated polymer material to promote angiogenesis. The drug-containing inclusion complex is prepared by encapsulating a 5α-reductase inhibitor; in the drug-containing inclusion complex, the molar concentration ratio of the 5α-reductase inhibitor to the angiogenic drug is 1:3-9; the angiogenic drug is deferoxamine or deferiprone; the 5α-reductase inhibitor is finasteride or dutasteride; the separation base liquid is composed of a polymer material, a gas initiator, and a solvent; the gas initiator is composed of an acid source and an alkali source; the mass volume ratio of the polymer material, acid source, alkali source, and solvent is 0.8-1.2g:0.1-0.15g:0.12-0.18g:3mL-4mL. In the aforementioned process of generating gas through microneedles, anhydrous ethanol is used as a solvent. However, this solvent cannot carry biomacromolecules such as proteins, peptides, or vaccines because ethanol may destroy the spatial structure of these biomacromolecules, thereby causing their inactivation or changing their immunogenicity. Therefore, this method has certain limitations. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the first objective of the present invention is to provide a method for preparing gas-driven dual-lumen microneedles. This method utilizes a green, zero-involvement organic solvent preparation process, avoiding the biocompatibility risks associated with traditional solvent evaporation methods. Furthermore, it overcomes the limitations of other gas-generating microneedles on the physicochemical properties of drugs, enabling the use of a wide range of drugs, including water-soluble and lipid-soluble drugs, biomacromolecules, and nanoparticles, while achieving precise cross-barrier delivery through gas propulsion.

[0006] The second purpose of the present invention is to provide a gas-driven dual-chamber microneedle whose dual-chamber modular structure supports orthogonal regulation of gas production dynamics and drug release behavior, and can be customized for different disease treatment scenarios (such as transdermal immunization, chronic disease management or local tumor treatment), with both broad-spectrum applicability and clinical transformation potential.

[0007] The third object of the present invention is to provide an application of a gas-driven double-lumen microneedle, which has the advantages of both broad-spectrum applicability and clinical transformation potential.

[0008] To achieve the above first object, the present invention provides the following technical solutions: A method for preparing a gas-driven double-lumen microneedle comprises the following steps: S1: preparing a needle tip solution, filling the needle tip solution into a microneedle mold, evacuating the mold, and drying the mold to obtain a blank microneedle with a first-level cavity and a second-level cavity; S2 uses a vacuum method or a centrifugal method to sequentially fill the first-level cavity with drug powder, and after filling the second-level cavity with gas-generating powder, a medical tape is adhered and fixed to the surface of the blank hole microneedle, and the mold is removed to obtain a gas-driven double-cavity microneedle.

[0009] Furthermore, in S1, the solute of the needle tip solution is one or a combination of chitosan, sodium hyaluronate, ethyl cellulose, sodium chondroitin sulfate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone, and the solvent of the needle tip solution is water.

[0010] Furthermore, in S1, the solutes of the needle tip solution are sodium carboxymethyl cellulose and sodium hyaluronate, and the molar ratio of sodium carboxymethyl cellulose to sodium hyaluronate is controlled to be 5-1:1-5.

[0011] Furthermore, in S1, the molar ratio of sodium carboxymethyl cellulose and sodium hyaluronate is controlled to be 5:1, 4:1, 2:1, 1:1, 1:2, 1:4, or 1:5.

[0012] Furthermore, in S1, the solute concentration of the needle tip solution is controlled to be 3-10 g / mL.

[0013] Furthermore, in S1, the solute concentration of the needle tip solution is controlled to be 3, 4, 5, 6, 7, 8, 9, or 10 g / mL.

[0014] Furthermore, in S1, the needle length of the needle tip area of the microneedle mold is 800 μm, the needle base diameter is 320 μm, the needle tip diameter is 10 μm, the needle tip distance is 700 μm, the number of needle tip arrays is 10*10, and the mold size is 10.3*10.3 mm.

[0015] Furthermore, in the S1, 100~300 μL of needle tip solution is first filled into the needle tip area of the microneedle mold, and then vacuumed for 5~30 minutes until the vacuum degree reaches -0.09~-0.01 MPa. After the needle tip solution completely fills the microneedle mold, the surface bubbles are scraped off, 100~200 μL of needle tip solution is added, and then transferred to a constant temperature and humidity drying oven, the ambient humidity is controlled at 10~50%, the ambient temperature is 30~60°C, and dried for 5~10 hours to obtain blank hole microneedles.

[0016] Furthermore, in the S1, 200 μL of needle tip solution is first filled into the needle tip area of the microneedle mold, and then vacuum is applied for 10 minutes until the vacuum degree reaches -0.07 MPa. After the needle tip solution completely fills the microneedle mold, the surface bubbles are scraped off, 150 μL of needle tip solution is added, and then the mold is transferred to a constant temperature and humidity drying oven, the ambient humidity is controlled at 30%, the ambient temperature is 40°C, and dried for 7 hours to obtain blank hole microneedles.

[0017] Furthermore, in S2, the drug powder is one or a combination of insulin, exenatide, paclitaxel, curcumin, borneol, huperzine A, asiatic acid, and huperzine A-borneol nanolipid carrier.

[0018] Furthermore, in S2, 3 g / mL trehalose is added to the drug powder as a freeze-drying protectant in advance, and the drug powder is pre-frozen in a -80°C refrigerator for 12 hours, and then placed in a vacuum freeze dryer for freeze-drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure is 0.1 mbar, the pre-frozen sample is placed in the freeze dryer, and the freeze-drying program is started and dried for 12 hours. After the end, nano-freeze-dried drug powder is obtained.

[0019] Furthermore, in S2, the gas generated by the gas-generating powder is one or a combination of oxygen, hydrogen and carbon dioxide.

[0020] Furthermore, in S2, the gas-generating powder is one or a combination of sodium peroxide, calcium peroxide, sodium percarbonate, ascorbic acid / sodium bicarbonate, tartaric acid / sodium carbonate, citric acid / sodium bicarbonate, and ascorbic acid / sodium bicarbonate / sodium carbonate.

[0021] Furthermore, in the step S2 , the gas generating powder is pre-crushed and passed through a 200-500 mesh sieve.

[0022] Furthermore, in S2, the gas generating powder is crushed and passed through a 400-mesh sieve in advance.

[0023] Furthermore, in S2, the vacuum degree of the vacuum method is controlled to be -0.09 to -0.01 MPa, and the vacuuming time is 5 to 30 minutes.

[0024] Furthermore, in S2, the vacuum degree of the vacuum method is controlled to be -0.07 MPa, and the vacuuming time is 10 minutes.

[0025] Furthermore, in S2, the centrifugal speed is controlled to be 1000-4000 r / min, the first centrifugation time is 5-30 min, and after the first centrifugation is completed, the direction is changed and centrifugation is continued for 5-30 min.

[0026] Furthermore, in S2, the centrifugal speed is controlled to be 3000 r / min, the first centrifugation time is 10 min, and after the first centrifugation is completed, the direction is changed and centrifugation is continued for 10 min.

[0027] Furthermore, in S2, the medical tape is one of cloth medical tape, transparent medical tape, and pressure-sensitive medical tape. The medical tape can be cut into 10.3*10.3 mm pieces so that the tape can completely fit the gas-driven dual-lumen microneedles on the microneedle mold.

[0028] To achieve the above first object, the present invention provides the following technical solutions: A gas-driven double-lumen microneedle is prepared by the above method.

[0029] To achieve the above first object, the present invention provides the following technical solutions: A gas-driven double-lumen microneedle is used, and the gas-driven double-lumen microneedle prepared by the above method is used in the preparation of drug delivery systems, vaccine delivery systems, medical beauty products, diagnostic monitoring markers, and gene therapy vector systems.

[0030] In summary, the beneficial technical effects of the present invention are: 1. This invention proposes an innovative powder form that integrates gas-generating powder into microneedles, completely avoiding the use of organic solvents in the preparation process. This method omits the tedious steps of organic solvent volatilization, such as lengthy drying or vacuum treatment. Because water is used as the solvent, the microneedles are not only naturally safe but also possess excellent biocompatibility. 2. The microneedle design of this invention is innovative, consisting of a Class I cavity and a Class II cavity. The Class I cavity is used to hold the drug powder layer, while the Class II cavity is used to hold the gas-generating powder. This unique gas-driven dual-cavity microneedle delivery system uses the gas generated by the gas-generating powder to create a local high-pressure environment, actively promoting the drug to penetrate the skin's natural resistance. 3. In the present invention, the gases generated by the gas-generating powder, such as oxygen, hydrogen, and carbon dioxide, can be naturally metabolized in the body after completing the drug propulsion task, eliminating the need to worry about chemical residues that may be caused by metal-based materials (such as magnesium); 4. The microneedle system of the present invention has a wide range of application potentials and can be loaded with different drug powders according to the treatment needs of different diseases. This design not only has a broad spectrum of applicability but also shows great potential in clinical transformation. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Schematic diagram of the structure of multiple blank hole microneedles prepared in Example 1 of the present invention.

[0032] Figure 2 Schematic diagram of the structure of a single blank hole microneedle prepared in Example 1 of the present invention.

[0033] Figure 3 Schematic diagram of the structure of the gas-driven double-lumen microneedle prepared in Example 1 of the present invention.

[0034] Figure 4 3 is a fluorescence distribution diagram of the gas-driven double-lumen microneedle prepared in Example 1 of the present invention, wherein ICG represents drug powder and RhB represents gas-generating powder.

[0035] Figure 5 Schematic diagram of in vitro transdermal release of microneedles in Experimental Example 1 of the present invention.

[0036] Figure 6 Schematic diagram of microneedle dissolution in Experimental Example 2 of the present invention.

[0037] Figure 7 1 is the escape latency of the Morris water maze under different training days in Test Example 3 of the present invention.

[0038] Figure 8 1 is the escape latency after modeling in different experimental groups of Test Example 3 of the present invention.

[0039] Figure 9 Graphs showing representative swimming trajectories of rats in the Morris water maze of each group in Experiment 3 of the present invention. DETAILED DESCRIPTION

[0040] In order to make the technical means, creative features, objectives and functions achieved by the present invention clearer and easier to understand, the present invention is further explained below with reference to the accompanying drawings and specific implementation methods.

[0041] Example 1: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is sodium carboxymethyl cellulose and hyaluronic acid in a molar ratio of 1:2, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 5 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, fill the needle tip area of the microneedle mold with 200 μL of needle tip solution, then transfer it to a vacuum drying oven and evacuate for 10 minutes until the vacuum degree reaches -0.07 MPa. After the needle tip solution completely fills the microneedle mold, scrape off the surface bubbles, add 150 μL of needle tip solution, and then transfer it to a constant temperature and humidity drying oven, control the ambient humidity to 30% and the ambient temperature to 40°C, and dry it for 7 hours to obtain blank hole microneedles; S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21 Poloxamer F68 and lecithin were weighed at a molar mass ratio of 3:1 and a concentration of 3 g / mL and dissolved in water at 70 ± 5 ° C to form an aqueous phase; monostearate and oleic acid were weighed at a molar mass ratio of 7:3 and a concentration of 2% (w / v, g / mL) and melted at 70 ± 5 ° C to form an oil phase; drugs huperzine A and borneol were added to the above oil phase, and the molar mass ratio of drugs to lipids was 1:10; the speed of the stirrer was set at 1200 rpm, and the water was stirred. The phases were added dropwise to the oil phase at the same temperature, and the colostrum was prepared by constant temperature magnetic stirring for 10 minutes. The obtained colostrum was placed in a cell disruptor and ultrasonicated for 10 minutes with the ultrasonic power set at 300W, with an operation time of 2 seconds and a rest time of 2 seconds. The average particle size of the solution was 89.6±0.7nm, the PDI was 0.219±0.03, the encapsulation efficiency was 82.67±0.42%, and the drug loading was 2.63±0.06%. First, prepare huperzine A-borneol nanolipid carrier as drug powder, add 3g / mL trehalose as lyoprotectant to the drug powder, and pre-freeze in a -80℃ refrigerator for 12 hours, then place it in a vacuum freeze dryer for freeze drying. When the freeze dryer temperature drops to -80℃ and the freeze-drying pressure reaches 0.1mbar, place the pre-frozen sample in the freeze dryer and start the freeze-drying program for 12 hours. After the end, nano-freeze-dried drug powder is obtained. Then, fill the first-level cavity with 2mg of nano-freeze-dried drug powder, transfer it to a vacuum drying oven, and evacuate for 10 minutes until the vacuum degree reaches -0.07Mpa and the drug powder completely fills the first-level cavity. S22: Ascorbic acid and sodium bicarbonate in a molar ratio of 1:1 are first prepared as gas-generating powders, which are then crushed through a 400-mesh sieve. The gas-generating powders are then filled into the Class II cavity and transferred to a vacuum drying oven for 10 minutes until the vacuum reaches -0.07 MPa and the Class II cavity is completely filled with the gas-generating powders. S23 first prepares pressure-sensitive medical tape as medical tape, and cuts the medical tape into 10.3*10.3 mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0042] Figure 1 This is the overall image of multiple blank hole microneedles prepared by the present invention. Figure 2 The morphology of a single blank hole microneedle prepared in the present invention shows that the microneedle has a good morphology and obvious holes.

[0043] Figure 3 This is an overall image of the gas-driven double-lumen microneedle. It can be seen that the hole at the needle tip has been completely filled, and the needle tip shape is complete and arranged regularly.

[0044] Figure 4 This is the fluorescence distribution diagram of the gas-driven dual-cavity microneedle prepared in the present invention. Indocyanine green (ICG) represents the drug powder and rhodamine B (RhB) represents the gas-generating powder. The gas-driven dual-cavity microneedle was prepared according to the method of this example. The distribution of fluorescent substances was observed by laser confocal microscopy. The results are as follows: Figure 4 The diagram shows: Area I represents the drug-loaded powder, and Area II represents the gas-generating powder. It can be seen that after the drug is loaded into the Level I cavity through vacuum, a secondary cavity is formed, into which the gas-generating powder can be well filled. Through the step-by-step negative pressure effect, the drug powder is first efficiently loaded into the Level I cavity, and then the gas-generating powder is filled into the Level II cavity formed at the proximal end of the needle body, and the gas-generating powder is loaded through vacuum.

[0045] Example 2: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is sodium carboxymethyl cellulose and hyaluronic acid in a molar ratio of 1:2, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 5 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, fill the needle tip area of the microneedle mold with 200 μL of needle tip solution, then transfer it to a vacuum drying oven and evacuate for 10 minutes until the vacuum degree reaches -0.07 MPa. After the needle tip solution completely fills the microneedle mold, scrape off the surface bubbles, add 150 μL of needle tip solution, and then transfer it to a constant temperature and humidity drying oven, control the ambient humidity to 30% and the ambient temperature to 40°C, and dry it for 7 hours to obtain blank hole microneedles; S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21 first prepares insulin as a drug powder, adds 3g / mL trehalose as a freeze-drying protective agent to the drug powder, and pre-freezes it in a -80°C refrigerator for 12 hours, then puts it into a vacuum freeze dryer for freeze drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure reaches 0.1mbar, the pre-frozen sample is placed in the freeze dryer, and the freeze-drying program is started and dried for 12 hours. After the end, nano-freeze-dried drug powder is obtained. Then, 2mg of nano-freeze-dried drug powder is filled in the first-level cavity and transferred to a centrifuge. The centrifugal speed is set to 3000r / min, and the first centrifugation time is 10min. After the first centrifugation, the direction is changed and centrifugation is continued for 10min until the drug powder completely fills the first-level cavity; S22: first prepare ascorbic acid / sodium bicarbonate with a molar ratio of 1:1 as a gas-generating powder, and crush it through a 400-mesh sieve. Then, fill the gas-generating powder into the second-level cavity and transfer it to a centrifuge. Set the centrifugal speed to 3000 r / min and the first centrifugation time to 10 minutes. After the first centrifugation, change the direction and continue centrifugation for 10 minutes until the gas-generating powder completely fills the second-level cavity. S23 first prepares pressure-sensitive medical tape as medical tape, and cuts the medical tape into 10.3*10.3 mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0046] Example 3: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is chitosan, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 3 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, 100 μL of the needle tip solution was filled into the needle tip area of the microneedle mold, and then the mold was transferred to a vacuum drying oven and evacuated for 5 min until the vacuum degree reached -0.09 MPa. After the needle tip solution completely filled the microneedle mold, the surface bubbles were scraped off, and 100 μL of the needle tip solution was added. The mold was then transferred to a constant temperature and humidity drying oven, and the ambient humidity was controlled at 10% and the ambient temperature was 30°C. It was dried for 5 h to obtain a blank hole microneedle. S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21 first prepared exenatide as a drug powder, added 3g / mL trehalose to the drug powder as a lyoprotectant, and pre-frozen in a -80°C refrigerator for 12 hours, then placed in a vacuum freeze dryer for freeze drying. When the freeze dryer temperature dropped to -80°C and the freeze-drying pressure reached 0.1mbar, the pre-frozen sample was placed in the freeze dryer and the freeze-drying program was started for 12 hours. After the end, nano-freeze-dried drug powder was obtained. Then, 2mg of nano-freeze-dried drug powder was filled into the first-level cavity, and the powder was transferred to a vacuum drying oven and vacuumed for 5 minutes until the vacuum reached -0.09Mpa and the drug powder completely filled the first-level cavity. S22 first prepares sodium peroxide as a gas-generating powder and crushes it through a 200-mesh sieve. Then, the gas-generating powder is filled into the Class II cavity and transferred to a vacuum drying oven. Vacuuming is carried out for 5 minutes until the vacuum degree reaches -0.09 MPa and the gas-generating powder completely fills the Class II cavity. S23 first prepares cloth medical tape as medical tape, and cuts the medical tape into 10.3*10.3mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0047] Example 4: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is ethyl cellulose, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 8 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, fill the needle tip area of the microneedle mold with 250 μL of needle tip solution, then transfer it to a vacuum drying oven and evacuate for 20 minutes until the vacuum degree reaches -0.05 MPa. After the needle tip solution completely fills the microneedle mold, scrape off the surface bubbles, add 150 μL of needle tip solution, and then transfer it to a constant temperature and humidity drying oven, control the ambient humidity to 20% and the ambient temperature to 40°C, and dry it for 8 hours to obtain blank hole microneedles; S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21: First, borneol is prepared as drug powder. 3 g / mL trehalose is added to the drug powder as a lyoprotectant. The drug powder is pre-frozen in a -80°C refrigerator for 12 hours and then placed in a vacuum freeze dryer for freeze drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure reaches 0.1 mbar, the pre-frozen sample is placed in the freeze dryer and the freeze-drying program is started for 12 hours. After the freeze-drying process is completed, nano-freeze-dried drug powder is obtained. 2 mg of nano-freeze-dried drug powder is then filled into the first-level cavity and transferred to a vacuum drying oven. Vacuuming is carried out for 20 minutes until the vacuum degree reaches -0.05 MPa and the drug powder completely fills the first-level cavity. S22 first prepares calcium peroxide as gas-generating powder and crushes it through a 300-mesh sieve. Then, the gas-generating powder is filled into the second-level cavity and transferred to a vacuum drying oven. Vacuuming is carried out for 20 minutes until the vacuum degree reaches -0.05 MPa and the gas-generating powder completely fills the second-level cavity. S23 first prepares transparent medical tape as medical tape, and cuts the medical tape into 10.3*10.3mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0048] Example 5: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is sodium chondroitin sulfate, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 10 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, 300 μL of the needle tip solution was filled into the needle tip area of the microneedle mold, and then the mold was transferred to a vacuum drying oven and evacuated for 30 min until the vacuum degree reached -0.01 MPa. After the needle tip solution completely filled the microneedle mold, the surface bubbles were scraped off, and 200 μL of the needle tip solution was added. The mold was then transferred to a constant temperature and humidity drying oven, and the ambient humidity was controlled at 50% and the ambient temperature was 60°C. The mold was dried for 10 h to obtain a blank hole microneedle. S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21 first prepares paclitaxel as drug powder, adds 3g / mL trehalose as a lyoprotectant to the drug powder, and pre-freezes it in a -80°C refrigerator for 12 hours, then places it in a vacuum freeze dryer for freeze drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure reaches 0.1mbar, the pre-frozen sample is placed in the freeze dryer and the freeze-drying program is started for 12 hours. After the freeze-drying process is completed, nano-freeze-dried drug powder is obtained. Then, 2mg of nano-freeze-dried drug powder is filled in the first-level cavity, and the powder is transferred to a vacuum drying oven and evacuated for 30 minutes until the vacuum reaches -0.01Mpa and the drug powder completely fills the first-level cavity. S22 first prepares sodium percarbonate as a gas-generating powder and crushes it through a 500-mesh sieve. Then, the gas-generating powder is filled into the Class II cavity and transferred to a vacuum drying oven. Vacuuming is carried out for 30 minutes until the vacuum degree reaches -0.01 MPa and the Class II cavity is completely filled with the gas-generating powder. S23 first prepares pressure-sensitive medical tape as medical tape, and cuts the medical tape into 10.3*10.3 mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0049] Example 6: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is hydroxypropyl cellulose, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 3 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, 100 μL of the needle tip solution was filled into the needle tip area of the microneedle mold, and then the mold was transferred to a vacuum drying oven and evacuated for 5 min until the vacuum degree reached -0.09 MPa. After the needle tip solution completely filled the microneedle mold, the surface bubbles were scraped off, and 100 μL of the needle tip solution was added. The mold was then transferred to a constant temperature and humidity drying oven, and the ambient humidity was controlled at 10% and the ambient temperature was 30°C. It was dried for 5 h to obtain a blank hole microneedle. S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21 first prepares curcumin as a drug powder, adds 3g / mL trehalose as a freeze-drying protective agent to the drug powder, and pre-freezes it in a -80°C refrigerator for 12 hours, then puts it into a vacuum freeze dryer for freeze drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure is 0.1mbar, the pre-frozen sample is placed in the freeze dryer, and the freeze-drying program is started and dried for 12 hours. After the end, nano-freeze-dried drug powder is obtained, and then 2mg of nano-freeze-dried drug powder is filled in the first-level cavity and transferred to a centrifuge. The centrifugal speed is set to 1000r / min, the first centrifugation time is 5min, and after the first centrifugation is completed, the direction is changed and centrifugation is continued for 5min until the drug powder completely fills the first-level cavity; S22: First, prepare tartaric acid / sodium carbonate as gas-generating powder, and crush it through a 200-mesh sieve. Then, fill the gas-generating powder into the second-level cavity and transfer it to a centrifuge. Set the centrifugal speed to 1000 r / min and the first centrifugation time to 5 minutes. After the first centrifugation, change the direction and continue centrifugation for 5 minutes until the gas-generating powder completely fills the second-level cavity. S23 first prepares cloth medical tape as medical tape, and cuts the medical tape into 10.3*10.3mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0050] Example 7: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is polyvinyl alcohol, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 8 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, fill the needle tip area of the microneedle mold with 250 μL of needle tip solution, then transfer it to a vacuum drying oven and evacuate for 20 minutes until the vacuum degree reaches -0.05 MPa. After the needle tip solution completely fills the microneedle mold, scrape off the surface bubbles, add 150 μL of needle tip solution, and then transfer it to a constant temperature and humidity drying oven, control the ambient humidity to 20% and the ambient temperature to 40°C, and dry it for 8 hours to obtain blank hole microneedles; S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21: First, prepare huperzine A as a drug powder, add 3 g / mL trehalose as a freeze-drying protective agent to the drug powder, and pre-freeze it in a -80°C refrigerator for 12 hours, then put it into a vacuum freeze dryer for freeze drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure reaches 0.1 mbar, put the pre-frozen sample into the freeze dryer, start the freeze-drying program and dry it for 12 hours. After the end, nano-freeze-dried drug powder is obtained. Then, fill the first-level cavity with 2 mg of nano-freeze-dried drug powder and transfer it to a centrifuge. Set the centrifugal speed to 2000 r / min and the first centrifugation time to 20 minutes. After the first centrifugation, change the direction and continue centrifugation for 20 minutes until the drug powder completely fills the first-level cavity. S22: First, prepare citric acid / sodium bicarbonate as gas-generating powder and crush it through a 300-mesh sieve. Then, fill the gas-generating powder into the second-level cavity and transfer it to a centrifuge. Set the centrifugal speed to 2000 r / min and the first centrifugation time to 20 min. After the first centrifugation, change the direction and continue centrifugation for 20 min until the gas-generating powder completely fills the second-level cavity. S23 first prepares transparent medical tape as medical tape, and cuts the medical tape into 10.3*10.3mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0051] Example 8: A gas-driven double-lumen microneedle disclosed in the present invention comprises the following steps: S1 prepares the needle tip solution and fills the needle tip solution into the microneedle mold, evacuates the mold, and dries the mold to obtain a blank hole microneedle with a first-level cavity and a second-level cavity. The specific implementation method is as follows: S11 prepares a needle tip solution, wherein the solute of the needle tip solution is polyvinyl pyrrolidone, the solvent of the needle tip solution is water, and the solute concentration of the needle tip solution is controlled to be 10 g / mL; S12 prepares a microneedle mold, wherein the needle tip area of the microneedle mold has a needle length of 800 μm, a needle base diameter of 320 μm, a needle tip diameter of 10 μm, a needle tip distance of 700 μm, a needle tip array number of 10*10, and a mold size of 10.3*10.3 mm; S13: First, 300 μL of the needle tip solution was filled into the needle tip area of the microneedle mold, and then the mold was transferred to a vacuum drying oven and evacuated for 30 min until the vacuum degree reached -0.01 MPa. After the needle tip solution completely filled the microneedle mold, the surface bubbles were scraped off, and 200 μL of the needle tip solution was added. The mold was then transferred to a constant temperature and humidity drying oven, and the ambient humidity was controlled at 50% and the ambient temperature was 60°C. The mold was dried for 10 h to obtain a blank hole microneedle. S2 uses vacuum or centrifugal method to fill drug powder in the first-level cavity and gas-generating powder in the second-level cavity, and then sticks medical tape to the surface of the blank cavity microneedle, demoulding, and obtaining a gas-driven dual-cavity microneedle; the specific implementation method is as follows: S21 first prepares asiatic acid as a drug powder, adds 3g / mL trehalose to the drug powder as a freeze-drying protective agent, and pre-freezes it in a -80°C refrigerator for 12 hours, then puts it into a vacuum freeze dryer for freeze-drying. When the freeze dryer temperature drops to -80°C and the freeze-drying pressure is 0.1mbar, the pre-frozen sample is placed in the freeze dryer, and the freeze-drying program is started and dried for 12 hours. After the end, nano-freeze-dried drug powder is obtained. Then, 2mg of nano-freeze-dried drug powder is filled in the first-level cavity and transferred to a centrifuge. The centrifugal speed is set to 4000r / min, the first centrifugation time is 30min, and after the first centrifugation is completed, the direction is changed and centrifugation is continued for 30min until the drug powder completely fills the first-level cavity; S22: first prepare ascorbic acid / sodium bicarbonate / sodium carbonate as a gas-generating powder, and crush it through a 500-mesh sieve. Then, fill the gas-generating powder into the second-level cavity and transfer it to a centrifuge. Set the centrifugal speed to 4000 r / min and the first centrifugation time to 30 minutes. After the first centrifugation, reverse the direction and continue centrifugation for 30 minutes until the gas-generating powder completely fills the second-level cavity. S23 first prepares pressure-sensitive medical tape as medical tape, and cuts the medical tape into 10.3*10.3 mm, then sticks and fixes the medical tape on the surface of the blank hole microneedle, demolds, and obtains a gas-driven double-cavity microneedle.

[0052] Comparative Example 1: A gas-driven dual-lumen microneedle disclosed in the present invention. The difference from Example 1 is that S22 is not included, and ordinary cavity drug-loaded microneedles are directly prepared.

[0053] Experimental Example 1: Transdermal performance of gas-driven dual-cavity microneedle and conventional cavity drug-loaded microneedle patches In vitro transdermal studies were conducted using conventional cavity-loaded drug-loaded microneedles (prepared in Comparative Example 1) and gas-driven dual-chamber microneedles (prepared in Example 1): Preparation of ex vivo mouse skin: First, use a pet razor to shave the hair on the back of the rat, then dislocate the cervical vertebrae to kill the rat, peel off the back skin, soak the skin in saline to clean it, and remove excess subcutaneous fat, blood vessels and other excess subcutaneous tissue. Wrap it in tin foil and store it in a -80℃ refrigerator for later use.

[0054] In vitro skin permeation studies were conducted using a classic Franz diffusion cell. Three groups were tested: huperzine A-borneol nanolipid carrier pneumatic microneedles (Hup A-Bor-NLC GMNs), huperzine A-borneol nanolipid carrier microneedles (Hup A-Bor-NLC MNs), and huperzine A ointment (Hup A-oint). The amount of ointment used was determined based on its drug content to ensure that the Hup A content in the ointment was consistent with that in the microneedle group. Each experiment was repeated three times. Sprague-Dawley rat skin was removed from a -80°C freezer and soaked in normal saline at room temperature for 1 hour. Excess surface fluid was then blotted with filter paper. Microneedles were inserted into the rat skin, and the skin was secured between a donor and a receiver cell. In a separate ointment group, the ointment was applied to the skin surface, and the skin was secured between a donor and a receiver cell.

[0055] Freshly prepared PBS (7.4) was added to the receiving cell with a volume of 7 mL. The instrument temperature was set at 37±1.0°C and the stirring speed was 150 rpm. 1 mL of release medium was collected in an EP tube for 1 m at 0.5, 1, 2, 4, 8, 12, 24 and 48 h, and 1 mL of fresh blank receiving solution was added. The receiving solution at each time point was subjected to HPLC analysis to calculate the cumulative release amount of HupA in each formulation.

[0056] Figure 5This figure shows the in vitro transdermal release of the microneedle patch. As shown in the figure, after 48 hours, the microneedle group showed greater drug penetration than the ointment group (43.464±5.073μg / cm2), demonstrating that microneedles can enhance drug transdermal penetration. The pneumatic microneedle group containing huperzine A-borneol nanolipid carriers began releasing drug as early as 0.5 hours, and after 48 hours, the drug permeation reached 153±5.57μg / cm2, significantly exceeding that of the huperzine A-borneol nanolipid carrier microneedle group (136.857±5.639μg / cm2). This suggests that the citric acid / sodium bicarbonate loaded within the microneedle cavity triggers CO2 generation through contact with tissue fluid, promoting deeper drug delivery via active penetration.

[0057] Experimental Example 2: Dissolution of Gas-Driven Dual-Cavity Microneedles and Ordinary Hole-Loaded Drug-Loaded Microneedles The dissolution was studied using conventional cavity-loaded drug-loaded microneedles (prepared in Comparative Example 1) and gas-driven dual-cavity microneedles (prepared in Example 1): The experiment was divided into two groups, namely, huperzine A-borneol nanolipid carrier pneumatic microneedle group (HBN-GMNs) and huperzine A-borneol nanolipid carrier microneedle group (HBN-MNs).

[0058] The aim was to investigate the gas production and drug penetration distance of a cavity-filled double-layer pneumatic microneedle patch. A 20% gelatin was used as a penetration model to simulate the moisture content of the skin. First, intact MNs from different groups were cut into 1×10 arrays and attached to a smooth vertical surface. Then, a 20% gelatin solid was attached to another smooth vertical surface. Both were placed under an optical microscope, allowing the microneedle tips to penetrate evenly into the gelatin. Dissolution and gas production of the microneedles were observed and photographed.

[0059] Figure 6 This is a schematic diagram of the dissolution of a microneedle patch. Upon penetration into a gelatin model, a pneumatic microneedle assembly containing huperzine A-borneol nanolipid carriers (HBN-GMNs) forms microchannels, enabling more effective drug penetration. Due to an acid-base chemical reaction, a large number of carbon dioxide bubbles are immediately generated between the backing and the needle body. The bubbles create a rocket-like "pumping" force that propels the needle body into the skin. The entire gas production process lasts approximately 2 minutes, and the drug delivery depth can reach 1190.45±97.90μm. In contrast, the HBN-GMN microneedle assembly dissolves within 30 seconds, with a drug delivery depth of only 108.52±23.15μm. This demonstrates that gas-driven dual-lumen microneedles are an effective method for continuously advancing drug delivery to deeper layers of skin tissue, facilitating drug penetration into deeper layers of skin tissue, enhancing transdermal permeability, and significantly promoting rapid drug release and transdermal delivery, providing strong support for the practical application of microneedle transdermal drug delivery.

[0060] Experimental Example 3: Pharmacodynamics of Gas-Driven Dual-Cavity Microneedles and Ordinary Hole-Loaded Drug Microneedles The Morris water maze test is a commonly used method to evaluate the spatial learning and memory abilities of neurodegenerative disease models. By recording indicators such as the swimming trajectory of experimental animals in the water maze and the time it takes to find the platform, their spatial learning, cognitive function, and memory recovery abilities can be objectively evaluated.

[0061] A short-term memory loss model in rats was established by inducing scopolamine hydrobromide and combined with the Morris water maze test to systematically evaluate the effects of gas-driven double-cavity microneedles and ordinary cavity drug-loaded microneedles on the spatial learning, cognitive function and memory recovery ability of rats.

[0062] Morris water maze test was conducted using ordinary cavity drug-loaded microneedles (prepared in Comparative Example 1) and gas-driven dual-lumen microneedles (prepared in Example 1): Experimental animals: Thirty SPF healthy male SD rats (200±20 g) were selected and a cognitive impairment model was established by intraperitoneal injection of scopolamine.

[0063] The rats were divided into normal group (Normol), model group (AD), oral gavage group (Ig), huperzine A-borneol nanolipid carrier microneedle group (HBN-MNs), and huperzine A-borneol nanolipid carrier pneumatic microneedle group (HBN-GMNs), with 6 rats in each group.

[0064] After one week of adaptive feeding, the rats in the control group were given PBS by gavage; the model group was given PBS by gavage; and the gavage group was given huperzine A in saline (1 mg / mL). After anesthesia and hair removal, the rats in the microneedle group were given a drug-loaded microneedle patch and secured with medical tape once daily for 11 consecutive days. On the 11th day of administration, all rats in the control group, except the control group, were intraperitoneally injected with scopolamine hydrobromide (1 mg / kg) to establish an Alzheimer's disease model with short-term memory loss. A spatial exploration experiment was performed 80 minutes later.

[0065] The Morris water maze consists of a circular pool (1.6 m in diameter, 0.4 m in height, and 0.25 m in depth), an infrared camera system, and an analysis system. The pool is divided into four equal quadrants, each with differently shaped markers on the walls to help the rats develop spatial memory. Before testing, water is filled into the pool and maintained at a temperature of 23 ± 1°C. A quadrant is randomly selected as the target quadrant, and a 10 cm diameter circular platform is placed approximately 2 cm underwater. Tracking stops if the rat reaches the platform or finds it within the specified time. The rat's swimming trajectory, distance traveled, time, and speed during this period are recorded to analyze changes in its escape latency to find the platform.

[0066] The experiment is divided into three phases: adaptive training, positioning cruise experiment and space exploration experiment.

[0067] (1) Adaptive training: During the experiment, a one-day adaptive training was conducted on the sixth day of drug administration. The circular platform in the pool was removed, and rats from each group were placed in the pool in the quadrant where the platform was located, facing the pool wall. They were allowed to perform adaptive swimming for 120 seconds and then returned to their cages.

[0068] (2) Positioning cruise experiment: Starting from the 7th day, rats were subjected to a 5-day positioning cruise experiment on a specific platform. Each rat was trained four times a day. The rats of each group were placed into the pool from four different quadrants with their heads facing the pool wall. They were taught to find the hidden platform. The swimming trajectory of the rats within 120 seconds and the time to find the platform were recorded, which was the escape latency. If the rats found the platform within 120 seconds, the timer was stopped. If the rats did not find the platform within 120 seconds, a wooden stick was used to guide the rats to the platform. The rats stayed on the platform for 15 seconds, and the 120 seconds were counted as the escape latency. After each rat completed one quadrant training, it was placed in a cage and replaced with the next rat for training.

[0069] (3) Spatial exploration experiment: On the 11th day of administration, rats were first given different preparations, and then 30 minutes after treatment, scopolamine hydrobromide (1 mg / kg) was intraperitoneally injected to establish an AD model with short-term memory deficit. After 80 minutes, the platform was removed and a spatial exploration experiment was conducted to record the representative swimming path of the rats, the frequency of crossing the original platform during the escape latency, and the time the rats stayed in the target quadrant to evaluate the ability to maintain the spatial location memory of the platform. Figure 7 is the escape latency in the Morris water maze under different training days. During the 4-day positioning navigation experiment, with the increase of training days, the escape latency of rats in each group gradually shortened, and they were able to find the platform in the water maze faster, indicating that the rats have acquired basic memory and spatial discrimination ability.

[0070] Figure 8 The following table shows the escape latency after modeling in different experimental groups. On day 11, after the rats were injected with scopolamine to establish a short-term memory deficit model, significant changes in the escape latency of the rats in each group were observed. The model group had the longest escape latency, indicating that memory was affected. This difference was significant compared to the normal group (p < 0.001). After oral administration or MNs treatment, the escape latency of rats decreased to varying degrees. The MNs group had a shorter escape latency than the oral administration group, and the HBN-GMNs group had the shortest escape latency (p < 0.001), approaching the level of the normal group.

[0071] Figure 9Figure 2 shows the representative swimming trajectories of the Morris water maze in each group of rats. The typical swimming trajectories show that compared with the normal group, the rats in the model group showed chaotic swimming trajectories, which also proved that the short-term memory deficit model was successfully established. The swimming trajectory of the HBN-GMNs group was relatively simple, indicating that the memory function of the rats was improved.

[0072] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for preparing a gas-driven dual-lumen microneedle, characterized by: The following steps are included: S1: preparing a needle tip solution, filling the needle tip solution into a microneedle mold, evacuating the mold, and drying the mold to obtain a blank microneedle with a first-level cavity and a second-level cavity; S2 uses a vacuum method or a centrifugal method to sequentially fill the first-level cavity with drug powder, and after filling the second-level cavity with gas-generating powder, a medical tape is adhered and fixed to the surface of the blank hole microneedle, and the mold is removed to obtain a gas-driven double-cavity microneedle.

2. The method for preparing a gas-driven dual-lumen microneedle according to claim 1, characterized in that: In S1, the solute of the needle tip solution is one or a combination of chitosan, sodium hyaluronate, ethyl cellulose, sodium chondroitin sulfate, sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone, and the solvent of the needle tip solution is water.

3. The method for preparing a gas-driven dual-lumen microneedle according to claim 2, characterized in that: In the S1, the solutes of the needle tip solution are sodium carboxymethyl cellulose and sodium hyaluronate, and the molar ratio of sodium carboxymethyl cellulose to sodium hyaluronate is controlled to be 5-1:1-5.

4. The method for preparing a gas-driven dual-lumen microneedle according to claim 1, characterized in that: In S1, the solute concentration of the needle tip solution is controlled to be 3-10 g / mL.

5. The method for preparing a gas-driven dual-lumen microneedle according to claim 1, characterized in that: In the S1, 100~300 μL of needle tip solution is first filled into the needle tip area of the microneedle mold, and then vacuum is applied for 5~30 min until the vacuum degree reaches -0.09~-0.01 MPa. After the needle tip solution completely fills the microneedle mold, the surface bubbles are scraped off, 100~200 μL of needle tip solution is added, and then the mold is transferred to a constant temperature and humidity drying oven, the ambient humidity is controlled at 10~50%, the ambient temperature is controlled at 30~60°C, and dried for 5~10 h to obtain blank hole microneedles.

6. The method for preparing a gas-driven dual-lumen microneedle according to claim 1, characterized in that: In S2, the drug powder is one or a combination of insulin, exenatide, paclitaxel, curcumin, borneol, huperzine A, asiatic acid, and huperzine A-borneol nanolipid carrier.

7. The method for preparing a gas-driven dual-lumen microneedle according to claim 1, characterized in that: In S2, the gas generated by the gas-generating powder is one or a combination of oxygen, hydrogen and carbon dioxide.

8. The method for preparing a gas-driven dual-lumen microneedle according to claim 1, characterized in that: In S2, the vacuum degree of the vacuum method is controlled to be -0.09~-0.01Mpa, and the vacuuming time is 5~30min; or, the centrifugal speed of the centrifugal method is controlled to be 1000~4000r / min, the first centrifugation time is 5~30min, and after the first centrifugation is completed, the direction is changed and centrifugation is continued for 5~30min.

9. A gas-driven dual-lumen microneedle, characterized by: The method is prepared according to any one of claims 1 to 8.

10. An application of a gas-driven double-lumen microneedle, characterized by: Application of the gas-driven double-lumen microneedle prepared by the method according to any one of claims 1 to 8 in the preparation of drug delivery systems, vaccine delivery systems, medical cosmetic products, diagnostic monitoring markers, and gene therapy vector systems.

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