Soluble microneedle patch for simulating extracellular matrix and preparation method of soluble microneedle patch

Abstract

The invention provides a soluble microneedle patch simulating an extracellular matrix and a preparation method thereof, the microneedle patch is mainly composed of sodium hyaluronate and collagen, the mass percentage of the sodium hyaluronate in the microneedle patch is 0.5-1%, and the mass percentage of the collagen in the microneedle patch is 2.5-5%. The preparation method disclosed by the invention is mild in reaction condition, simple, convenient and easy to operate, and the sodium hyaluronate is used for moisturizing and locking water and providing moisture and moistening degree required by skin; the collagen supports and maintains the elasticity and compactness of the skin, and can promote the synthesis of the collagen; sodium hyaluronate and collagen are mixed for use, the stability and durability of the microneedle patch can be enhanced, meanwhile, the microneedle serving as a novel transdermal drug delivery dosage form almost rarely touches a corium layer with rich nerves, and pain in the use process is greatly relieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of high polymer materials, in particular to a soluble microneedle patch simulating extracellular matrix and a preparation method thereof. BACKGROUND

[0002] Extracellular matrix (ECM) is a non-cellular substance distributed in the extracellular space, mainly including 5 types of insoluble macromolecules: collagen, non-collagen protein, elastin, glycosaminoglycan and proteoglycan. These substances form a complex network structure, support and connect tissue structure, regulate tissue occurrence and cell physiological activity, constitute the microenvironment necessary for cell survival, and through the different fine and ingenious entanglement of intermolecular, form various exquisite three-dimensional structures, endow the skin with elasticity and tensile strength, and make the skin look full and energetic.

[0003] Hyaluronic acid is a kind of acidic mucopolysaccharide in which a disaccharide derivative is connected by β-1, 3-glycosidic bond and β-1, 4-glycosidic bond with β-D-glucuronic acid and N-acetyl-D-glucosamine as repeating units. Hyaluronic acid is widely distributed in the human body, such as joint cartilage, dermal layer of skin and other tissues. Hyaluronic acid has a special water retention effect and is the best moisturizing substance in nature so far, and is called an ideal natural moisturizing factor. It can improve skin nutrient metabolism, make the skin tender, smooth, wrinkle-free, increase elasticity and prevent aging. While moisturizing, it is also a good transdermal absorption promoter. The "hyaluronic acid" we refer to in daily life usually refers to its stable sodium salt form, i.e. sodium hyaluronate. Due to the enhanced stability, it is more convenient to store and transport, and thus is more widely used in medicine, cosmetics and various health care products. Collagen is a biological polymer and a structural protein of extracellular matrix. 70% of subcutaneous dermal tissue is composed of collagen, which is the most abundant protein in the human body. Type I collagen is relatively hard and has thicker fibers, which is used to support skin hardness and make the skin firm. Type III collagen is smaller and has a soft structure with elasticity, which is used to support skin tenderness. Type XVII collagen anchors the epidermis and dermis, which is crucial for maintaining the structural integrity and signal transmission between the epidermis and the dermis. Collagen accounts for about 30% of the total amount of human protein, equivalent to 6% of the body weight. It is present in every tissue and organ of the body and is the main component for maintaining the shape and structure of skin and tissue organs. It is also an important raw material for repairing damaged tissues. In addition, collagen can prevent diseases and improve physical fitness, and is very helpful for beauty and health.

[0004] In recent years, microneedle technology has developed rapidly and has been gradually applied to the field of beauty. As a new transdermal drug delivery system, microneedles are generally 100-1000 μm in length, and almost rarely touch the nerve-rich dermis, greatly reducing the pain during use. The early microneedles are made of silicon, metal or other materials by microelectronic manufacturing technology or micro-molding technology, among which the silicon and metal hard microneedles have the probability of breaking, and the broken needle tips remain in the epidermis, causing skin allergy, and even disfigurement in severe cases. In view of these shortcomings of early microneedles, more and more people begin to research and develop green and environmentally friendly, high cell compatibility, and self-dissolving degradable biological microneedles. Hyaluronic acid microneedles and collagen microneedles are among them, but simply using a certain active substance to prepare a filler has the problems of unsatisfactory effect or short shelf life.

[0005] Through retrieval, no patent disclosure related to the patent application of the present application has been found. SUMMARY

[0006] 1. A soluble microneedle patch which is not tissue extracted and simulates extracellular matrix, characterized by being composed of a microneedle array and a substrate, and the raw material comprising: polysaccharide, collagen.

[0007] 2. The soluble microneedle patch according to claim 1, wherein the weight ratio of the polysaccharide and the collagen is: polysaccharide 0.5-1%, collagen 2.5-5%.

[0008] 3. The soluble microneedle patch according to any one of claims 1-2, wherein the polysaccharide is selected from the group consisting of hyaluronic acid, chondroitin sulfate, fucoidan, keratan sulfate, heparin sulfate, and salts thereof, preferably hyaluronic acid or a salt thereof, more preferably sodium hyaluronate.

[0009] 4. The soluble microneedle patch according to any one of claims 1-2, wherein the collagen is selected from the group consisting of type I collagen or oligopeptides thereof, type II collagen or oligopeptides thereof, type III collagen or oligopeptides thereof, type V collagen and oligopeptides thereof, type XI collagen and oligopeptides thereof, type XVII collagen and oligopeptides thereof, preferably type I collagen, type III collagen and type XVII collagen, more preferably recombinant type I collagen, recombinant type III collagen and recombinant type XVII collagen.

[0010] 5. A method for preparing the soluble microneedle patch according to any one of claims 1-4, characterized in that the preparation method comprises the following steps:

[0011] S1. Dissolve polysaccharide in phosphate buffer, perform 121℃ moist heat sterilization to obtain solution A;

[0012] S2. Take collagen dissolved in phosphate buffer solution, put it in a syringe, filter sterilization with 0.22 μm filter membrane, get solution B;

[0013] S3. Take solution A obtained in S1 and solution B obtained in S2, mix them evenly with mechanical stirring, then centrifuge to remove bubbles, get mold liquid;

[0014] S4. Inject a small amount of mold liquid into the microneedle mold, centrifuge, fill the needle holes with mold liquid, then suck part of the mold liquid as the base part of the microneedle and lay it on the microneedle mold;

[0015] S5. After drying completely, demolding, the soluble microneedle patch simulating extracellular matrix is obtained.

[0016] The preparation method of the soluble microneedle patch according to claim 5, characterized in that:

[0017] In step S1, the preparation method of the phosphate buffer solution is as follows: take 8.5 g of sodium chloride, 2.2 g of disodium hydrogen phosphate, and 0.1 g of sodium dihydrogen phosphate, dissolve them in 800 mL of purified water, adjust the pH of the solution to 7.4 with HCl, and then add purified water to make up to 1 L, and the phosphate buffer solution is obtained.

[0018] The preparation method of the soluble microneedle patch according to claim 5, characterized in that:

[0019] In step S1, the polysaccharide has a molecular weight of 2000 kDa-2500 kDa, the mass percentage of polysaccharide in the solution is 1-2%, and the moist heat sterilization time is 15 min.

[0020] The preparation method of the soluble microneedle patch according to claim 5, characterized in that:

[0021] In step S2, the mass percentage of collagen in the solution is 5-10%, and the ratio of recombinant type I collagen, recombinant type III collagen, and recombinant type XVII collagen is 1:3:1.

[0022] The preparation method of the soluble microneedle patch according to claim 5, characterized in that:

[0023] In step S3, the volume ratio of solution A to solution B is 1:1, and the centrifugation speed is 4500 r / min for 1 min.

[0024] The preparation method of the soluble microneedle patch according to claim 5, characterized in that:

[0025] In step S4, the height of the microneedle is 100 µm-800 µm, and after the mold liquid is injected into the microneedle mold, it is centrifuged at 4500 r / min for 3 times, 1 min each time, to fill the needle tip completely.

[0026] The preparation method of the dissolvable microneedle patch according to claim 5, characterized in that:

[0027] In step S5, the drying temperature is 40 DEG C, and the time is 4h.

[0028] The preparation method has the advantages of mild reaction conditions, simple operation, and the like, and the sodium hyaluronate can provide moisture and moisturizing degree required by the skin, the collagen can support and maintain elasticity and tightness of the skin and promote synthesis of self collagen, and the mixture of the sodium hyaluronate and the collagen can enhance stability and durability of the microneedle patch, so that the effect is more significant and persistent. BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 are different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application;

[0030] Figure 2 are a mechanical property test diagram of the dissolvable microneedle prepared in example 2 of the present application and a diagram of the microneedle patch dissolved after insertion into pigskin;

[0031] Figure 3 are diagrams of expression amounts of genes related to promotion of collagen synthesis of different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application;

[0032] Figure 4 are quantitative data of promotion of cell growth of different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application;

[0033] Figure 5 are diagrams of live / dead staining of co-culture of different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application and cells;

[0034] Figure 6 are diagrams of states of promotion of cell migration of different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application;

[0035] Figure 7 are quantitative data of promotion of cell migration of different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application;

[0036] Figure 8 are Masson staining diagrams of promotion of collagen regeneration of different dissolvable microneedle patches prepared in examples 1-2 and comparative examples 1-2 of the present application. DETAILED DESCRIPTION

[0037] The application is further described below in connection with examples, which are illustrative and not limiting, and cannot be used to limit the protection scope of the application. The raw materials used in the application are conventional commercially available products unless otherwise specified. The sodium hyaluronate used in the examples is purchased from Huaxi Biotechnology Co., Ltd.; the recombinant collagen type I / III is purchased from Zhuji Juyuan Biotechnology Co., Ltd.; the recombinant collagen type XVII is purchased from Jiangsu Chuangjian Medical Technology Co., Ltd.; the polydimethylsiloxane (PDMS) microneedle mold is purchased from Taizhou Weixi Medical Technology Co., Ltd. The methods used in the application are conventional methods in the art unless otherwise specified, and the quality of each substance used in the application is conventional.

[0038] Example 1

[0039] Take 8.5 g of sodium chloride, 2.2 g of disodium hydrogen phosphate, and 0.1 g of sodium dihydrogen phosphate, and dissolve them in 800 mL of purified water. Adjust the pH of the solution to 7.4 with HCl, and then add purified water to make up to 1 L to obtain a phosphate buffer. Take sodium hyaluronate with a molecular weight of 2000 kDa-2500 kDa and dissolve it in the phosphate buffer at a mass percentage of 1% to obtain solution A. Take collagen and dissolve it in the phosphate buffer at a mass percentage of 5%, wherein the ratio of recombinant collagen type I, recombinant collagen type III, and recombinant collagen type XVII is 1:3:1. Filter sterilize with a 0.22 μm filter to obtain solution B. Physically mix solution A and solution B at a volume ratio of 1:1, centrifuge at 4500 r / min for 1 min to remove bubbles, and obtain a mold injection solution. Uniformly spread a small amount of the mold injection solution on the polydimethylsiloxane microneedle mold, place it in a centrifuge, and centrifuge at 4500 r / min for 3 times, 1 min each time, so that the mold injection solution fills the microneedle mold needle holes. Then, take a certain amount of the mold injection solution as the microneedle base part, and uniformly spread it on the microneedle mold. After the microneedles are dried at 40℃ for 4 h, demold to obtain a microneedle patch.

[0040] Example 2

[0041] Take 8.5 g of sodium chloride, 2.2 g of disodium hydrogen phosphate, 0.1 g of sodium dihydrogen phosphate, dissolve in 800 mL of purified water, adjust the pH of the solution to 7.4 with HCl, and then add purified water to 1 L to obtain a phosphate buffer. Take sodium hyaluronate with a molecular weight of 2000 kDa-2500 kDa and dissolve it in the phosphate buffer at a mass percentage of 2%. Sterilize the solution at 121°C for 15 min to obtain solution A. Take collagen and dissolve it in the phosphate buffer at a mass percentage of 10%, wherein the ratio of recombinant type I collagen, recombinant type III collagen and recombinant type XVII collagen is 1:3:1. Filter sterilize with a 0.22 μm filter to obtain solution B. Physically mix solution A and solution B at a volume ratio of 1:1, centrifuge at 4500 r / min for 1 min to remove bubbles, and obtain a molding liquid. Uniformly spread a small amount of the molding liquid on a polydimethylsiloxane microneedle mold, place it in a centrifuge and centrifuge at 4500 r / min for 3 times, 1 min each time, so that the molding liquid fills the microneedle mold needle holes. Then, a certain amount of the molding liquid is sucked and used as a microneedle base part, and is uniformly spread on the microneedle mold. After the microneedle is dried at 40°C for 4 h, demolding is performed, and a microneedle patch is obtained.

[0042] Comparative Example 1

[0043] Take 8.5 g of sodium chloride, 2.2 g of disodium hydrogen phosphate, 0.1 g of sodium dihydrogen phosphate, dissolve in 800 mL of purified water, adjust the pH of the solution to 7.4 with HCl, and then add purified water to 1 L to obtain a phosphate buffer. Take sodium hyaluronate with a molecular weight of 2000 kDa-2500 kDa and dissolve it in the phosphate buffer at a mass percentage of 2%. Sterilize the solution at 121°C for 15 min to obtain solution A. Take collagen and dissolve it in the phosphate buffer at a mass percentage of 10%, wherein the ratio of recombinant type I collagen, recombinant type III collagen and recombinant type XVII collagen is 1:3:1. Filter sterilize with a 0.22 μm filter to obtain solution B. Physically mix solution A and solution B at a volume ratio of 1:1, centrifuge at 4500 r / min for 1 min to remove bubbles, and obtain a molding liquid. Uniformly spread a small amount of the molding liquid on a polydimethylsiloxane microneedle mold, place it in a centrifuge and centrifuge at 4500 r / min for 3 times, 1 min each time, so that the molding liquid fills the microneedle mold needle holes. Then, a certain amount of the molding liquid is sucked and used as a microneedle base part, and is uniformly spread on the microneedle mold. After the microneedle is dried at 40°C for 4 h, demolding is performed, and a microneedle patch is obtained.

[0044] Comparative Example 2

[0045] Take 8.5 g of sodium chloride, 2.2 g of disodium hydrogen phosphate, 0.1 g of sodium dihydrogen phosphate, and dissolve them in 800 mL of purified water. Adjust the pH of the solution to 7.4 with HCl, and then add purified water to make up to 1 L to obtain a phosphate buffer. Take sodium hyaluronate with a molecular weight of 2000 kDa-2500 kDa and dissolve it in the phosphate buffer at a mass percentage of 1%. Sterilize the solution at 121°C for 15 min to obtain solution A. Take collagen and dissolve it in the phosphate buffer at a mass percentage of 10%, wherein the ratio of recombinant type III collagen and recombinant type XVII collagen is 3:1. Filter sterilize with a 0.22 μm filter to obtain solution B. Physically mix solution A and solution B at a volume ratio of 1:1, and centrifuge at 4500 r / min for 1 min to remove bubbles to obtain a molding solution. Uniformly spread a small amount of the molding solution on a polydimethylsiloxane microneedle mold, and place it in a centrifuge for centrifugation at 4500 r / min for 3 times, each time for 1 min, so that the molding solution fills the microneedle mold needle holes. Then, a certain amount of the molding solution is sucked and uniformly spread on the microneedle mold as a microneedle base part. After the microneedles are dried at 40°C for 4 h, demolding is performed to obtain a microneedle patch.

[0046] Performance test

[0047] Mechanical performance test

[0048] Sealing film puncture test: press the microneedle with the thumb fingertip with moderate force (about 5-10 N) to directly puncture a layer of sealing film. If it passes smoothly, add another layer; in this way, record the number of layers punctured to judge the mechanical performance of the microneedle. The results are shown in Figure 2 Example 2 microneedle can puncture 5 layers of sealing film in turn, indicating that the microneedle has a certain mechanical strength.

[0049] Pig ex vivo skin puncture experiment: take ex vivo pig skin, press the microneedle with the thumb to puncture the healthy undamaged pig ex vivo skin, remove the microneedle after staying in the skin for 20 min, immediately dye with 2% methylene blue solution, and observe whether the skin surface punctured by the microneedle is dyed blue and whether there is a blue dot matrix. The results are shown in Figure 2 The microneedle can successfully puncture the pig ex vivo skin and leave a fine pore for methylene blue to penetrate and dye, and the microneedle patch has almost dissolved due to contact with moisture in the skin, indicating that the microneedle of Example 2 can effectively break through the human skin barrier.

[0050] Real-time quantitative PCR (qRT-PCR) technology for detecting gene expression

[0051] After human skin fibroblasts (HSF) are co-cultured with microneedles for a predetermined time, the intracellular messenger RNA (mRNA) is extracted by a kit, and then reverse transcribed into cDNA, which is amplified by a qRT-PCR reaction, and finally the fluorescence values of each group after amplification are compared to know the expression of the corresponding genes. The experimental results are analyzed by 2 -∆∆Ct method.

[0052] As shown in Figure 3 , both Example 1-2 and Comparative Example 1-2 can up-regulate the expression of collagen synthesis-related genes col I and col III, and Example 2 promotes the expression of related genes most significantly.

[0053] Cell growth test

[0054] The HSF with good activity is made into a single cell suspension and counted to make the cell density 10 4 x 10 5 cells / mL, inoculated in a 96-well plate, 200 μL of cell suspension is added to each well, and after the cells are attached, the old culture medium is removed and a new culture medium containing microneedle molding solution (microneedle molding solution: culture medium = 1:4) is added. Each sample of Example 1-2 and Comparative Example 1-2 is set up in 5 replicates, and placed in a 37°C, 5% CO2 incubator for continuous culture for 24h, 48h, and 72h. At each time point, 20 μL of MTT solution (prepared with PBS with pH = 7.4) is added to the corresponding wells, and then cultured for another 4h. The plate is quickly inverted, and the supernatant is discarded. 150 μL of DMSO is added to each well, and shaken for 10 min to dissolve the MTT crystals. The absorbance value of each well at 490 nm is detected by an enzyme-linked detector, and a cell-free well is set as a control group for zero adjustment. The average value of 5 wells is taken. The cell growth column chart is plotted with culture time and absorbance value as coordinate axes as shown in Figure 2 . In addition, HSF is co-cultured with microneedles for 24h, then the culture medium is discarded and washed twice with PBS solution, then the cells are stained according to the instructions in the live / dead cell staining kit, and observed and recorded using an inverted fluorescence microscope.

[0055] As shown in Figure 4 , the absorbance of the examples is higher than that of the comparative examples, and the absorbance of Example 2 is the highest, representing that its ability to promote cell growth is the most significant. In addition, as shown in Figure 5 , the number of living cells of Example 2 has a significant growth trend.

[0056] Cell migration test

[0057] First, use a marker pen to evenly draw horizontal lines on the back of a 6-well plate with a ruler, one line every 0.5-1.0 cm, crossing the well. At least 3 lines cross the well. Add about 5 x 10 5The number of cells varies depending on the cells, and the basic number is overnight. On the second day, the gun head was placed vertically to the ruler, and the scratch was drawn as vertically as possible to the back horizontal line. The gun head should be vertical and cannot be inclined. The cells were washed with PBS for 3 times to remove the scratched cells. The serum-free medium without microneedle injection solution was used as the control group, and the microneedle injection solutions of examples 1-2 and comparative examples 1-2 were used as the test groups. The samples were placed in a 37℃, 5% CO2 incubator. The samples were sampled at 0h and 24h, and photographed. The scratch area was measured by ImageJ-win64 software, and the cell migration rate of each group was calculated. Cell migration rate = total area of migrated cells in fixed scratch area / initial scratch area x 100%.

[0058] As shown in Figure 6 , 7 , the cell migration rates of the examples were higher than those of the comparative examples, and the cell migration promoting ability of example 2 was the strongest. The microneedle patch simulating the extracellular matrix cooperated to form a three-dimensional biological scaffold network, which not only provided a biomimetic microenvironment for cell growth, but also exhibited excellent cell growth and migration promoting ability, providing double regeneration power for facial rejuvenation.

[0059] Histological analysis

[0060] The biological activity of different microneedle patches was evaluated by in vivo experiments. Fifteen 6-8 week old male Kunming mice were randomly divided into a blank control group, an example 1 group, an example 2 group, a comparative example 1 group and a comparative example 2 group, with 3 mice in each group. The microneedle patches were pressed into the back of each animal in the example and comparative example groups, and were fixed with medical tape. After half an hour, the tape was removed, and the patches were used twice a week. Tissue samples were collected at 0 and 14 days for Masson staining.

[0061] As shown in Figure 8 , after 14 days, the collagen fiber edges in the dermis of the blank control group had almost no change, while the collagen fibers in the dermis of the example 1-2 and comparative example 1-2 groups increased significantly, and the collagen fiber enhancement in the example 2 group was the most obvious.

[0062] Although the examples of the present application are disclosed for illustrative purposes, those skilled in the art can understand that various alternatives, changes and modifications are possible without departing from the spirit and scope of the present application and the appended claims, and therefore the scope of the present application is not limited to the disclosed content of the examples.

Claims

1. A soluble microneedle patch that simulates extracellular matrix and is not extracted from tissue, characterized in that It consists of a microneedle array and a substrate, and the raw materials include: polysaccharide and collagen.

2. The soluble microneedle patch according to claim 1, wherein the weight ratio of the polysaccharide to the collagen is: 0.5-1% polysaccharide and 2.5-5% collagen.

3. The soluble microneedle patch according to any one of claims 1 to 2, wherein the polysaccharide is selected from the group consisting of hyaluronic acid, chondroitin sulfate, seaweed polysaccharide, keratan sulfate, heparin sulfate, and salts thereof, preferably hyaluronic acid or a salt thereof, more preferably sodium hyaluronate.

4. The soluble microneedle patch according to any one of claims 1 to 2, wherein the collagen is selected from the group consisting of type I collagen or its oligopeptides, type II collagen or its oligopeptides, type III collagen or its oligopeptides, type V collagen and its oligopeptides, type XI collagen and its oligopeptides, and type XVII collagen and its oligopeptides, preferably type I collagen, type III collagen, and type XVII collagen, and more preferably recombinant type I collagen, recombinant type III collagen, and recombinant type XVII collagen.

5. A method for preparing a soluble microneedle patch according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: S1. Dissolve the polysaccharide in phosphate buffer and sterilize by moist heat at 121°C to obtain Solution A. S2. Dissolve collagen in phosphate buffered saline (PBS), place in a syringe, and sterilize by filtration using a 0.22 μm filter to obtain Solution B. S3 take the solution A obtained from S1 and the solution B obtained from S2 using mechanical stirring and thoroughly mixed and centrifuged to remove bubbles to obtain a molding liquid; S4. A small amount of molding liquid is injected into the microneedle mold, centrifuged, so that the molding liquid fills the pinhole, and then part of the molding liquid is drawn as the microneedle base portion and spread on the microneedle mold; S5. After complete drying, demold the microneedle patch to obtain a soluble microneedle patch that mimics the extracellular matrix.

6. The method for preparing the soluble microneedle patch according to claim 5, wherein: In step S1, the phosphate buffer solution is prepared by dissolving 8.5 g of sodium chloride, 2.2 g of disodium hydrogen phosphate, and 0.1 g of sodium dihydrogen phosphate in 800 mL of purified water, adjusting the pH of the solution to 7.4 with HCl, and then adding purified water to make the volume to 1 L to obtain the phosphate buffer solution.

7. The method for preparing the soluble microneedle patch according to claim 5, wherein: In step S1, the molecular weight of the polysaccharide is 2000 kDa-2500 kDa, the mass percentage of the polysaccharide in the solution is 1-2%, and the moist heat sterilization time is 15 minutes.

8. The method for preparing the soluble microneedle patch according to claim 5, wherein: In step S2, the mass percentage of the collagen in the solution is 5-10%, wherein the ratio of recombinant type I collagen, recombinant type III collagen and recombinant type XVII collagen is 1:3:

1.

9. The method for preparing the soluble microneedle patch according to claim 5, wherein: In step S3, the volume ratio of solution A to solution B is 1:1, and the mixture is centrifuged at 4500 r / min for 1 min.

10. The method for preparing the soluble microneedle patch according to claim 5, wherein: In step S4, the microneedle height is 100 μm-800 μm. After the molding liquid is injected into the microneedle mold, it is centrifuged at 4500 rpm for 3 times, each time for 1 minute, to ensure that the needle tip is completely filled.

11. The method for preparing the soluble microneedle patch according to claim 5, wherein: In step S5, the drying temperature is 40° C. and the drying time is 4 hours.

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