Microneedle, microneedle patch, and method of manufacturing microneedle

Abstract

Some embodiments of the present invention provide a microneedle including a support portion, a needle tip portion, and an adhesive layer. The needle tip portion is disposed on the support portion and includes an active material. The adhesive layer is disposed between the support portion and the needle tip portion, and includes a viscous material and a viscosity-reducing substance dispersed in the viscous material. The release position and the release dosage of the active substances can be accurately controlled, the active substances are dispersed, more needle point parts are reserved in the punctured part, and the content of the active substances released into the skin of the needle point parts is increased. Also provided in some embodiments of the present invention are microneedle patches and methods of making microneedles.

Description

Technical Field

[0001] The present invention relates to a microneedle, a microneedle patch and a method for manufacturing the microneedle. Background Art

[0002] Skin aging is the most obvious external manifestation of human aging. Whether it is endogenous skin aging caused by aging or exogenous aging caused by ultraviolet radiation, the collagen content in the dermis of the skin will decrease, causing skin atrophy, wrinkles, and loss of elasticity. Commonly used dermal fillers in clinical practice mainly include collagen or hyaluronic acid (HA) as temporary fillers, and poly-L-lactic acid (PLLA) as semi-permanent fillers. Since dermal fillers are mainly in the form of injections, they need to be performed by doctors in person, and the effect will vary depending on the doctor's operating skills.

[0003] Injectable dosage forms generally have problems such as bruising, hematoma and pain due to the difficulty in controlling the injection location or injection dose (for example, too deep or too much).

[0004] For example, clinically, PLLA filler Sculptra usually causes skin bruising, redness, swelling, itching and pain after injection, requiring about a week of postoperative recovery, and daily massage after injection to evenly distribute the PLLA microstructure in the skin and avoid uneven collagen proliferation at the injection site. In addition, the PLLA used in Sculptra is an irregular flake crystal with sharp corners, which can cause considerable irritation in the skin tissue and easily cause inflammatory reactions, leading to adverse symptoms such as papules, nodules, and foreign body granulomas at the injection site.

[0005] Therefore, how to provide a dosage form and a manufacturing method for releasing active substances (such as the dermal filler mentioned above) that can reduce side effects, reduce operation risks and improve filling effects is a problem to be solved. Summary of the invention

[0006] Some embodiments of the present invention provide a microneedle, comprising: a support portion, a needle tip portion, and an adhesive layer. The needle tip portion is disposed on the support portion and contains an active substance. The adhesive layer is disposed between the support portion and the needle tip portion and contains: a viscous material and a viscosity-reducing substance dispersed in the viscous material.

[0007] In some embodiments, the support comprises a support material comprising an adhesive substance, a non-adhesive substance, or a combination thereof.

[0008] In some embodiments, the viscous material comprises hyaluronic acid (HA), sodium glutamate, polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethylcellulose (CMC), gelatin, or a combination thereof.

[0009] In some embodiments, the non-stick material comprises chitosan, polylactic acid (PLA), poly(glycolicacid) (PGA), polycaprolacone (PCL), polyetheretherketone (PEEK), poly(lactic-co-glycolicacid) (PLGA), polymethyl methacrylate (PMMA), polyethylene (PE), or a combination thereof.

[0010] In some embodiments, the viscous material comprises hyaluronic acid, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamic acid, gelatin, water-soluble sugars, or a combination thereof.

[0011] In some embodiments, the viscosity reducing substance is a hydrophilic co-solvent.

[0012] In some embodiments, the viscosity reducing substance comprises sucrose, lactose, mannitol, mannose, galactose, glucose, fructose, maltose, trehalose, polyethylene glycol, or a combination thereof.

[0013] In some embodiments, based on the total weight of the adhesive layer being 100%, the weight percentage of the viscosity reducing substance in the adhesive layer is 5% to 50%.

[0014] In some embodiments, based on the total weight of the adhesive layer being 100%, the weight percentage of the viscosity reducing substance in the adhesive layer is 5% to 25%.

[0015] In some embodiments, the needle tip further comprises a biodegradable material, and the biodegradable material comprises hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamine, starch, gelatin, chitosan, carboxymethyl cellulose or a combination thereof.

[0016] In some embodiments, the active material comprises hyaluronic acid, polylactic acid (PLA), polyglycolic acid, polylactic-co-glycolic acid, polycaprolactone (PCL), calcium hydroxide apatite (CaHA), collagen, carboxymethyl cellulose, bioceramics, or a combination thereof.

[0017] In some embodiments, the active agent is in the form of microspheres.

[0018] Some embodiments of the present invention provide a microneedle patch, comprising: the aforementioned microneedles and a patch fixed to a supporting portion of the microneedles.

[0019] Some embodiments of the present invention provide a method for manufacturing microneedles, comprising: mixing a needle tip material, an active substance and water to obtain a needle tip solution; filling the needle tip solution into a microneedle mold to obtain a molded needle tip solution; drying the molded needle tip solution to obtain a needle tip; mixing a viscous material, a viscosity-reducing substance and water to obtain an adhesive layer solution; filling the adhesive layer solution into a microneedle mold retaining a needle tip so that the adhesive layer solution covers the needle tip to obtain a molded adhesive layer solution; providing a support portion; placing the support portion into the microneedle mold retaining the needle tip and the molded adhesive layer solution so that the molded adhesive layer solution adheres to the support portion and the needle tip; and drying the molded adhesive layer solution to obtain a microneedle.

[0020] In some embodiments, the total weight of the needle tip solution is 100%, and the weight percentage of the needle tip material in the needle tip solution is 3% to 50%.

[0021] In some embodiments, the needle tip material comprises a biodegradable material.

[0022] In some embodiments, the step of filling the microneedle mold with a needle tip solution comprises: covering the microneedle mold with the needle tip solution; and using a first needle tip pressing device to initially pressurize the needle tip solution so that the needle tip solution fills the microneedle mold to obtain a shaped needle tip solution; and the step of drying the shaped needle tip solution comprises: drying the shaped needle tip solution for the first time so that the shaped needle tip solution is initially solidified; and using a second needle tip pressing device to perform a second pressurization on the shaped needle tip solution so that the initially solidified shaped needle tip solution is further shaped; and a second drying of the further shaped needle tip solution to obtain a needle tip.

[0023] In some embodiments, the total weight of the adhesive layer solution is 100%, the weight percentage of the adhesive material in the adhesive layer solution is 3% to 60%, and the weight percentage of the viscosity reducing substance in the adhesive layer solution is 0.15% to 30%.

[0024] In some embodiments, the total weight of the adhesive layer solution is 100%, and the weight percentage of the viscosity reducing substance in the adhesive layer solution is 3% to 15%.

[0025] In some embodiments, the viscosity reducing substance comprises sucrose, lactose, mannitol, mannose, galactose, glucose, fructose, maltose, trehalose, polyethylene glycol, or a combination thereof.

[0026] In some embodiments, the step of filling the microneedle mold with the needle tip with the adhesive layer solution comprises using an adhesive layer pressing device to pressurize the molded adhesive layer solution so that the molded adhesive layer solution covers the needle tip.

[0027] In some embodiments, the step of providing a support part comprises: mixing a support part material and water to obtain a support part solution; filling the support part solution into a support part mold to obtain a shaped support part solution; and drying the shaped support part solution to obtain a support part.

[0028] In some embodiments, the step of filling the support part solution into the support part mold comprises: covering the support part solution on the support part mold; and using a first support part pressing device to initially pressurize the support part solution so that the support part solution fills the support part mold to obtain a molded support part solution; and wherein the step of drying the molded support part solution comprises: drying the molded support part solution so that the molded support part solution is initially solidified; using a second support part pressing device to perform a second pressurization on the molded support part solution so that the initially solidified molded support part solution is compacted on the bottom of the support part mold; covering the support part solution on the support part mold again; using the first support part pressing device to pressurize the support part solution so that the supported part solution covered again fills the support part mold and covers the compacted molded support part solution to obtain a second molded support part solution; and drying the second molded support part solution so that the second molded support part solution is fixed as a support part.

[0029] In some embodiments, the step of providing the support portion comprises: placing a support portion material on a support portion mold; heating the support portion material so that the support portion material melts and fills the support portion mold; and cooling the support portion material to obtain the support portion.

[0030] The microneedle of the present invention, by storing the active substance in the needle tip and using the support part to further extend the puncture depth of the needle tip, can make the needle tip containing a specific dose of active substance remain in a specific part of the skin and slowly dissolve as the viscous material dissolves, thereby accurately controlling the release position and release dose of the active substance. In addition, because the active substance is dispersed to each puncture unit in the microneedle, the release position is dispersed, which can reduce the risk of adverse symptoms caused by excessive concentrated release of the active substance.

[0031] In addition, by adding a viscosity-reducing substance to the adhesive layer, the proportion of the needle tip adhering to the support portion can be reduced when the microneedle is removed from the puncture site, thereby retaining more of the needle tip in the puncture site, increasing the amount of active substances released from the needle tip into the skin, improving the transfer efficiency, and thereby enhancing the effect of stimulating collagen regeneration. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to make the above and other objects, features, advantages and embodiments of the present invention more clearly understood, the accompanying drawings are described as follows:

[0033] Figure 1A Schematic diagrams of microneedles in some embodiments of the present invention are presented.

[0034] Figure 1B Schematic diagrams of microneedle patches in accordance with some embodiments of the present invention are presented.

[0035] Figure 2 A flow chart presenting a method of making microneedles in some embodiments of the present invention.

[0036] Figure 3A The present invention shows the microneedles manufactured according to Example 1 of the present invention (Part A and Part B), and the puncture test results after the microneedles puncture pig skin and the support part is removed from the pig skin (Part C is the support part after removal, and Part D is the pig skin surface).

[0037] Figure 3B The puncture test results of two kinds of microneedles puncturing pig skin using an adhesive layer including a viscosity-reducing substance and a microneedle without a viscosity-reducing substance, wherein Part A and Part B are the puncture test results of the adhesive layer not including a viscosity-reducing substance (trehalose), Part A is the support part after removal, and Part B is the pig skin surface; Part C and Part D are the puncture test results of the adhesive layer including a viscosity-reducing substance (trehalose), Part C is the support part after removal, and Part D is the pig skin surface, Figure 3B Part C and Part D of Figure 3A Part C and Part D of

[0038] Figure 4 The present invention shows that after puncturing pig skin or rat skin with the microneedle of Example 1, the release of fluorescently labeled PLLA microspheres (PLLAMPs) in skin tissue sections is observed.

[0039] Figure 5 The present invention shows that after the rat skin was punctured with the microneedle of Example 1, the release of PLLAMPs at the microneedle puncture site was detected by fluorescence at different time points.

[0040] Figure 6 as well as Figure 7 The immunohistochemical staining images of the microneedle puncture area or the intradermal injection area at 4 weeks after microneedle puncture or intradermal injection of rat skin are presented. Figure 6 The results of hematoxylin-eosin staining are shown in Figure 2. Figure 7 This is the result of Masson's trichrome staining. Figure 6 as well as Figure 7 The group injected with phosphate buffered saline (PBS) intradermally was referred to as the PBSID group, the group injected with microneedles with hyaluronic acid (excluding PLLA microspheres) at the needle tip was referred to as the HAMNs group, the group injected with PLLA microspheres intradermally was referred to as the PLLAMPsID group, and the group injected with the microneedles of Example 1 was referred to as the PLLAMP-MNs group. DETAILED DESCRIPTION

[0041] In order to make the description of the present invention more detailed and complete, the following describes in detail the implementation methods and specific embodiments of the present invention; however, this is not the only form of implementing or using the specific embodiments of the present invention. The various embodiments disclosed below can be combined or replaced with each other in beneficial situations, and other embodiments can be added to one embodiment without further description or explanation. In the following description, many specific details will be described in detail to enable the reader to fully understand the following embodiments. However, the embodiments of the present invention can be practiced without such specific details.

[0042] In this document, unless the context specifically limits the article, "a", "an" and "the" may refer to one or more. It will be further understood that "comprising", "including", "having" and similar words used in this document specify the features, regions, integers, steps, operations, elements and / or components described therein, but do not exclude other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0043] As used herein, the term "about" means a value of a given amount that varies within 5% of the value (e.g., ±1%, ±2%, ±3%, ±4%, ±5%). These values ​​are examples only and are not intended to be limiting. It should be understood that the term "about" may mean a percentage of the value of a given amount as interpreted by one of ordinary skill in the art in view of the teachings herein.

[0044] In this document, unless otherwise defined (for example, with emphasis on "excluding"), the terms "higher than", "lower than", "greater than", "less than", etc. are intended to include the relative values ​​referred to, for example, "higher than" 0.1 mg means including 0.1 mg.

[0045] Although a series of operations or steps are used below to illustrate the method disclosed herein, the order shown in these operations or steps should not be construed as a limitation of the present invention. For example, certain operations or steps may be performed in different orders and / or simultaneously with other steps. In addition, it is not necessary to perform all operations, steps and / or features to implement the embodiments of the present invention. Furthermore, each operation or step described herein may include several sub-steps or actions.

[0046] Please refer to Figure 1A Some embodiments of the present invention provide a microneedle 100, comprising a support portion 110, a needle tip portion 120, and an adhesive layer 130. The needle tip portion 120 is disposed on the support portion 110 and comprises an active substance 122. The adhesive layer 130 is disposed between the support portion 110 and the needle tip portion 120, and comprises a viscous material 134 and a viscosity-reducing substance 132 dispersed in the viscous material 134.

[0047] The microneedle 100 of the present invention, by storing the active substance 122 in the needle tip 120 and using the support part 110 to further extend the puncture depth of the needle tip 120, can make the needle tip 120 containing a specific dose of active substance 122 slowly dissolve in a specific part of the skin as the viscous material 134 dissolves, thereby accurately controlling the release position and release dose of the active substance 122, and dispersing the active substance 122, reducing the risk of adverse symptoms caused by excessive concentrated release of the active substance 122. Since the release position and release dose are uniformly controlled by the structural design of the microneedle 100, the operation threshold can be lowered, and the difference in subcutaneous filling effect caused by differences in operator operation techniques can be avoided.

[0048] Furthermore, by adding the viscosity reducing substance 132 to the adhesive layer 130, the proportion of the needle tip 120 adhering to the support portion 110 can be reduced when the microneedle 100 is removed from the puncture site, thereby retaining more of the needle tip 120 in the puncture site, increasing the amount of active substance 122 in the needle tip 120 released into the skin, and thereby enhancing the effect of stimulating collagen regeneration.

[0049] In some embodiments, the support portion 110 includes a support portion material, and the support portion material includes a viscous substance, a non-viscous substance, or a combination thereof. In some embodiments, the viscous substance is a water-soluble substance, and the non-viscous substance is a non-water-soluble substance. The viscous substance is soluble in water or tissue fluid, for example, the solubility in each milliliter of water is higher than 0.1 mg. Relatively speaking, the solubility of the non-viscous substance in each milliliter of water is lower than (not including) 0.1 mg. In some embodiments, the viscous substance includes hyaluronic acid, sodium polyglutamate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, gelatin, or a combination thereof. In some embodiments, the non-viscous substance includes chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polyetheretherketone, polylactic acid-glycolic acid copolymer, polymethyl methacrylate, polyethylene, or a combination thereof. It can be understood that the use of a non-viscous substance as the support portion material can reduce the situation in the skin tissue fluid where the viscosity of the support portion 110 is increased due to the absorption of water vapor, and the softening of the support portion 110 affects the removal effect.

[0050] In some embodiments, the viscous material 134 comprises hyaluronic acid, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamic acid, gelatin, water-soluble carbohydrates or a combination thereof. In some embodiments, the viscosity-reducing substance 132 is a hydrophilic cosolvent, for example, the viscosity-reducing substance 132 comprises sucrose, lactose, mannitol, mannose, galactose, glucose, fructose, maltose, trehalose, polyethylene glycol or a combination thereof. By adding the viscosity-reducing substance 132, the viscosity of the adhesive layer 130 and the support portion 110 can be adjusted, so that the support portion 110 is easier to separate from the needle tip 120, the amount of the needle tip 120 adhering to the support portion 110 is reduced, and the situation that the needle tip 120 is removed together with the support portion 110 or is left on the skin surface is avoided when the support portion 110 is removed.

[0051] In some embodiments, the total weight of the adhesive layer 130 is 100%, and the weight percentage of the viscosity reducing substance 132 in the adhesive layer 130 is 5% to 50%, such as 5%, 10%, 15%, 20%, 30%, 40%, 50% or values ​​in the aforementioned range, and the weight percentage of the viscous material 134 is 50% to 95%, such as 50%, 60%, 70%, 80%, 90%, 95% or values ​​in the aforementioned range. If the weight percentage of the viscosity reducing substance 132 is too high or the weight percentage of the viscous material 134 is too low, the effect of the adhesive layer 130 in fixing the needle tip 120 and the support part 110 is limited, and the probability of the needle tip 120 and the support part 110 separating increases when taking the microneedle 100. If the weight percentage of the viscosity reducing substance 132 is too low or the weight percentage of the viscous material 134 is too high, the adhesive layer 130 is too viscous, and when the microneedle 100 is removed from the puncture site, the probability of the needle tip 120 sticking to the support portion 110 increases. In some embodiments, the total weight of the adhesive layer 130 is 100%, and the weight percentage of the viscosity reducing substance 132 in the adhesive layer 130 is 5% to 25%.

[0052] In some embodiments, the active substance 122 of the needle tip 120 includes hyaluronic acid, polylactic acid (e.g., poly-L-lactic acid (PLLA) or poly-D,L Lactic-Acid (PDLLA)), polyglycolic acid, polylactic-glycolic acid copolymer, polycaprolactone, calcium hydroxide apatite, collagen, carboxymethyl cellulose, bioceramics (mineral crystals with biocompatibility), or a combination thereof. Those skilled in the art can select a specific active substance 122 according to needs. It is understandable that, since the microneedle 100 can fix the puncture depth through the regulation of the support portion 110, and control the uniform release of an appropriate amount of active substance 122 from the needle tip 120, the microneedle 100 can avoid foreign matter and inflammatory reactions caused by excessive aggregation of the released active substance 122, thereby avoiding adverse reactions such as nodules, papules, granulomas, etc., and has good safety.

[0053] For example, polylactic acid can be used as a subcutaneous filler to stimulate collagen regeneration. When polylactic acid is used as the active substance 122 of the needle tip 120, the micro-wound healing stimulation generated after the puncture of the microneedle 100 and the characteristic of polylactic acid inducing collagen regeneration can be combined to strengthen the collagen regeneration effect. In addition, the active substance 122 uses collagen or hyaluronic acid as a temporary filler. After puncturing the skin, it will be quickly dissolved and absorbed by the skin, and the wrinkle removal effect can only last from a few months to about a year and a half, and the maintenance time is limited. In contrast, if the active substance 122 uses polylactic acid, which can be used as a semi-permanent filler, the duration of the filling effect can be extended.

[0054] In some embodiments, the active substance 122 is in the form of microspheres. Compared with the sharp edges of non-spherical forms (such as irregular shapes), the microsphere form can reduce irritation to the skin and reduce the occurrence of adverse reactions.

[0055] In some embodiments, the needle tip 120 further comprises a biodegradable material, and the biodegradable material comprises hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamine, starch, gelatin, chitosan, carboxymethyl cellulose or a combination thereof. When the support portion 110 is removed from the puncture site, the needle tip 120 is retained in the skin, and the biodegradable material can be dissolved in the skin, while releasing the active substance 122. In one embodiment, the biodegradable material is hyaluronic acid, which can have a good skin absorption effect, and hyaluronic acid can also accelerate wound recovery and shorten the recovery period.

[0056] In some embodiments, the total weight of the needle tip 120 is 100%, the weight percentage of the active substance 122 in the needle tip 120 is 5% to 50% (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or values ​​in the aforementioned intervals), and the weight percentage of the biodegradable material in the needle tip 120 is 50% to 95% (e.g., 50%, 60%, 70%, 80%, 90%, 95% or values ​​in the aforementioned intervals).

[0057] In some embodiments, the microneedle 100 has a plurality of puncture units 100S, each puncture unit 100S includes a needle tip unit 120S, an adhesive layer unit 130S, and a support unit 110S, and each puncture unit 100S is connected to each other via a support connection unit 110L. In some embodiments, a microneedle 100 of 1 square centimeter has 60 to 120 puncture units 100S, such as 60, 70, 80, 90, 100, 110, 120, or a value in the aforementioned interval, and contains 0.1 mg to 5 mg of active substance 122, such as 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2 mg, 2.2 mg, 2.4 mg, 2.6 mg, 2.8 mg, 3 mg, 3.2 mg, 3.4 mg, 3.6 mg, 3.8 mg, 4 mg, 4.2 mg, 4.4 mg, 4.6 mg, 4.8 mg, 5 mg or values ​​in the aforementioned range to achieve better collagen regeneration effects while avoiding adverse reactions caused by excessive amounts of active substance 122.

[0058] In some embodiments, the height H1 of the microneedle 100 (from the surface 114 of the support portion 110 (or the upper surface of the base portion of the support portion 110) to the top surface of the needle tip portion 120) is 300 μm to 1500 μm, for example, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1000 μm, 1100 μm, 1200 μm, 1300 μm, 1400 μm, 1500 μm, or values ​​in the aforementioned intervals. In some embodiments, the height H2 of the support portion 110 (from the interface between the support portion 110 and the adhesive layer 130 to the surface 114 of the support portion 110) is 300 μm to 1200 μm, for example, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, 1000 μm, 1100 μm, 1200 μm, or values ​​in the aforementioned intervals. If the height H1 or the height H2 is too small, the puncture position is too shallow, and the active substance 122 cannot be released in the dermis. If the height H1 or the height H2 is too long, the puncture wound is too deep, which prolongs the healing time. In some embodiments, the width W of the base surface of the puncture unit 100S (the interface between the support unit 110S and the support connection unit 110L) projected on the X-axis is approximately 200 microns to 500 microns, such as 200 microns, 300 microns, 400 microns, 500 microns or a value in the aforementioned range. If the width W is too small, the mechanical strength of the support portion 110 is insufficient, and the risk of fracture is high. If the width W is too large, the material cost increases.

[0059] Next, please refer to Figure 1B Some embodiments of the present invention provide a microneedle patch 200, comprising a microneedle 100 and a patch 210 fixed to a support portion 110 of the microneedle 100. The patch 210 is fixed to a lower surface 112 of the support portion 110, has adhesiveness, and can adhere to the skin during puncture to fix the microneedle 100 in the skin, thereby preventing the microneedle 100 from moving unexpectedly and causing the wound to expand.

[0060] Next, please refer to Figure 2 (Combined with reference Figure 1A ), some embodiments of the present invention provide a method 300 for manufacturing a microneedle 100.

[0061] First, in step S310 , the needle tip material, the active substance 122 and water are mixed to obtain a needle tip solution.

[0062] In some embodiments, the needle tip material comprises a biodegradable material, such as hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamine, starch, gelatin, chitosan, carboxymethyl cellulose or a combination thereof. In some embodiments, the weight percentage of the needle tip material in the total weight of the needle tip solution is 3% to 50%, such as 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or a value in the aforementioned interval. If the weight percentage is too low, the needle tip solution is too dilute, and the needle tip 120 is difficult to form and easy to deform. If the weight percentage is too high, the needle tip solution is too thick and difficult to operate.

[0063] In some embodiments, the active substance 122 comprises hyaluronic acid, polylactic acid (e.g., poly L-lactic acid (PLLA) or poly D-lactic acid (PDLLA)), polyglycolic acid, polylactic-glycolic acid copolymer, polycaprolactone, calcium hydroxyapatite, collagen, carboxymethyl cellulose, bioceramics (mineral crystals with biocompatibility), or a combination thereof. In some embodiments, the weight percentage of the active substance 122 in the total weight of the needle tip solution is 1% to 50%, such as 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or values ​​in the foregoing intervals. In some embodiments, the weight percentage of the active substance 122 in the total weight of the needle tip solution is 5 to 30%.

[0064] Step S320, filling the needle tip solution into the microneedle mold to obtain a molded needle tip solution.

[0065] In some embodiments, step S320 includes covering the needle tip solution on the microneedle mold; and using the first needle tip pressing device to initially pressurize the needle tip solution so that the needle tip solution fills the microneedle mold to obtain a molded needle tip solution. It can be understood that because the needle tip solution may be too thick, it cannot fit the contour inside the microneedle mold well when covering the microneedle mold. By initially pressurizing the needle tip solution, it can be ensured that the needle tip solution fills the microneedle mold and improves the manufacturing yield of the needle tip 120. In some embodiments, the pressing component of the first needle tip pressing device is planar, so as to facilitate pushing the needle tip solution into the microneedle mold.

[0066] Step S330 , drying the shaped needle tip solution to obtain the needle tip 120 .

[0067] In some embodiments, the shaped needle tip solution is dried for the first time to make the shaped needle tip solution initially solidified; and the shaped needle tip solution is pressurized for the second time using the second needle tip pressing device to further shape the initially solidified shaped needle tip solution; and the shaped needle tip solution is dried for the second time to obtain the needle tip 120. The design of the step of further shaping by the second needle tip pressing device after initial solidification can make the needle tip solution more consistent with the contour inside the microneedle mold, thereby improving the manufacturing yield of the needle tip 120. In some embodiments, the pressing component of the second needle tip pressing device is, for example, tooth-shaped, which can penetrate into the microneedle mold, so that the needle tip solution can better match the contour inside the microneedle mold. In some embodiments, step S330 includes performing the first and second drying in an environment of 30°C to 60°C (e.g., 30°C, 40°C, 50°C, 60°C or values ​​in the aforementioned range), wherein the time of the first drying is shorter than the time of the second drying.

[0068] Step S340, mixing the viscous material 134, the viscosity reducing substance 132 and water to obtain an adhesive layer solution. The description of the viscous material 134 and the viscosity reducing substance 132 can be referred to in Figure 1A The relevant records are not repeated here.

[0069] In some embodiments, the total weight of the adhesive layer solution is 100%, the weight percentage of the viscous material 134 in the adhesive layer solution is 3% to 60% (for example, 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60% or values ​​in the aforementioned intervals), and the weight percentage of the viscosity reducing substance 132 in the adhesive layer solution is 0.15% to 30% (for example, 0.15%, 0.3%, 0.5%, 1%, 5%, 10%, 15%, 20%, 25%, 30% or values ​​in the aforementioned intervals). If the weight percentage of the viscous material 134 is too high or the weight percentage of the viscosity-reducing substance 132 is too low, the adhesive layer solution will be too viscous and difficult to operate, and the adhesive layer 130 will be too viscous to adhere to the needle tip 120, which will cause the problem of the needle tip 120 sticking to the support part 110 when the support part 110 is removed after the microneedle 100 punctures the skin. If the weight percentage of the viscous material 134 is too low or the weight percentage of the viscosity-reducing substance 132 is too high, the effect of the adhesive layer 130 in fixing the needle tip 120 and the support part 110 is limited, and the probability of the needle tip 120 and the support part 110 separating increases when the microneedle 100 is taken out. In some embodiments, the total weight of the adhesive layer solution is 100%, and the weight percentage of the viscosity-reducing substance 132 in the adhesive layer solution is 3% to 15%.

[0070] In step S350 , the adhesive layer solution is filled into the microneedle mold with the needle tip 120 retained therein, so that the adhesive layer solution covers the needle tip 120 , thereby obtaining a molded adhesive layer solution.

[0071] In some embodiments, step S350 includes using an adhesive layer pressing device to pressurize the shaped adhesive layer solution so that the shaped adhesive layer solution covers the needle tip portion 120. In some embodiments, the adhesive layer pressing device is the same as the first needle tip pressing device.

[0072] Step S360: providing the support unit 110.

[0073] The support part 110 may be prepared in different ways according to the difference of the support part material. For example, the following two preparation methods may be provided according to the difference of the solubility of the support part material in water.

[0074] When the support material is soluble in water or tissue fluid (for example, the solubility in each milliliter of water is higher than 0.1 mg), in some embodiments, step S360 includes mixing the support material and water to obtain a support solution; filling the support solution into a support mold to obtain a shaped support solution; and drying the shaped support solution to obtain a support part 110.

[0075] In some embodiments, the total weight of the support solution is 100%, and the weight percentage of the support material in the support solution is 30% to 70%, such as 30%, 40%, 50%, 60%, 70% or values ​​in the aforementioned range. If the weight percentage is too low, the support solution is too dilute, and the support 110 is difficult to form and easily deformed. If the weight percentage is too high, the support solution is too thick and difficult to operate.

[0076] In some embodiments, the step of filling the support part solution into the support part mold comprises: covering the support part solution on the support part mold; and using a first support part pressing device to initially pressurize the support part solution so that the support part solution fills the support part mold to obtain a shaped support part solution. In some embodiments, the pressing component of the first support part pressing device is flat to facilitate pushing the support part solution into the support part mold. In one embodiment, the first support part pressing device is the same as the first needle tip pressing device.

[0077] In some embodiments, the step of drying the molded support part solution comprises: drying the molded support part solution to allow the molded support part solution to be initially solidified; using a second support part pressing device to perform a second pressurization on the molded support part solution to allow the initially solidified molded support part solution to be compacted on the bottom of the support part mold; covering the support part solution on the support part mold again; using a first support part pressing device to pressurize the support part solution to allow the covered support part solution to fill the support part mold and cover the compacted molded support part solution to obtain a second molded support part solution; and drying the second molded support part solution to allow the second molded support part solution to be fixed as the support part 110.

[0078] In some embodiments, the steps of drying the molded support solution and drying the second molded support solution comprise drying in an environment of 30°C to 60°C (eg, 30°C, 40°C, 50°C, 60°C, or values ​​in the foregoing range).

[0079] The design of the step of further shaping by the second support part pressing device after preliminary curing can make the support part solution more consistent with the contour inside the support part mold, thereby improving the manufacturing yield of the support part 110. In some embodiments, the pressing component of the second support part pressing device is, for example, tooth-shaped, which can penetrate into the support part mold, so that the support part solution can better fit the contour inside the support part mold. In some embodiments, the second support part pressing device is the same as the second needle tip pressing device.

[0080] When the support material is poorly soluble or insoluble in water or tissue fluid (for example, the solubility in each milliliter of water is less than (not including) 0.1 mg, for example, polylactic acid), in some embodiments, step S360 includes setting the support material on the support mold; heating the support material so that the support material melts and fills the support mold; and cooling the support material to obtain the support part 110.

[0081] In some embodiments, heating the support material comprises heating the support material at a temperature of 150°C to 250°C, e.g., 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, or values ​​in the foregoing intervals, in a vacuum environment to ensure that the support material is fully melted.

[0082] In step S370 , the support portion 110 is placed in the microneedle mold retaining the needle tip portion 120 and the molded adhesive layer solution, so that the molded adhesive layer solution adheres the support portion 110 and the needle tip portion 120 .

[0083] In some embodiments, step S370 includes applying force to the support portion 110 to push the support portion 110 into the microneedle mold, so that the adhesive layer solution bonds the needle tip portion 120 and the support portion 110 .

[0084] Step S380 , drying the molded adhesive layer solution to obtain the microneedle 100 .

[0085] In some embodiments, the molded adhesive layer solution is dried in an environment of 30°C to 40°C (e.g., 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, or values ​​in the foregoing intervals) for 15 minutes to 45 minutes (e.g., 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, or values ​​in the foregoing intervals).

[0086] To further illustrate the microneedles, microneedle patches and microneedle manufacturing methods provided by various embodiments of the present invention, the following examples are performed. It should be noted that the following examples are provided for demonstration purposes only and are not intended to limit the present invention.

[0087] 1. Preparation method of microneedles

[0088] 1.1. Preparation of needle tip

[0089] First, the needle tip solution (containing an appropriate amount of left-handed polylactic acid microspheres (PLLA microparticles, PLLAMPs), hyaluronic acid and water, wherein the weight percentage of hyaluronic acid in the needle tip solution is 33%) is spread on the microneedle mold, and the first needle tip pressing device (the pressing component is a flat type) is used to apply force to the needle tip solution so that the needle tip solution fills the microneedle mold to shape the needle tip solution. The microneedle mold containing the needle tip solution is placed in an environment of about 37°C for drying, so that the needle tip solution is initially solidified. Then, the second needle tip pressing device (the pressing component can penetrate into the interior of the microneedle mold) is used to pressurize the needle tip solution for a second time, and the needle tip solution in the microneedle mold is pressed forward to the needle tip, so that the needle tip solution is further shaped. Then, the microneedle mold containing the needle tip solution is placed in an environment of about 37°C to dry the needle tip solution for the second time, so that the needle tip solution is dried and solidified, and the needle tip contained in the microneedle mold is obtained.

[0090] 1.2. Preparation of the support

[0091] Since the support material can be a viscous substance or a non-viscous substance, the preparation methods when the support material is a viscous substance or a non-viscous substance are respectively exemplified below.

[0092] 1.2.1 The support part is made of non-sticky material (taking polylactic acid as an example)

[0093] The PLA wire is laid flat on the support part mold, and heated at 200°C for 3 hours in a vacuum at a pressure of 1 inch of mercury. The pressure is then released, so that the PLA wire melts and fills the support part mold. After the polylactic acid wire is cooled to room temperature and solidified into a support part, the support part is removed from the support part mold to obtain a support part.

[0094] 1.2.2 The support part is made of viscous material (such as hyaluronic acid)

[0095] The support part solution (hyaluronic acid hydrogel formed by dissolving 50% hyaluronic acid in water by weight) is spread on the support part mold (the inner contour of the support part mold at least partially matches the contour of the inner near opening end of the microneedle mold), and the first support part pressing device (the pressing part is a flat type) is used to apply force to the support part solution so that the support part solution fills the support part mold. Then, the support part mold containing the support part solution is placed in an environment of about 37°C and dried for several minutes so that the support part solution is initially solidified. Then, the second support part pressing device (the pressing part can penetrate into the support part mold) is used to pressurize the support part solution for a second time, and the support part solution in the support part mold is compacted forward to the bottom of the support part mold. The support part solution is spread on the support part mold again, and the first support part pressing device (the pressing part is a flat type) is used to apply force to the support part solution for several seconds so that the support part solution fills the support part mold and covers the previously compacted support part solution. Next, the support part mold is placed at room temperature overnight to allow the support part solution to dry, and then the support part can be removed from the support part mold to obtain the support part.

[0096] 1.3. Material testing of adhesive layer

[0097] The adhesive layer is used to connect the needle tip and the support part. In the experimental process, it was found that when the adhesive layer solution only contained hyaluronic acid, the needle tip was easily adhered to the support part when the support part was removed, resulting in loss of the needle tip and reducing the efficiency of active substance delivery.

[0098] To avoid sticking of the adhesive layer, different materials (hyaluronic acid + water, or water + hyaluronic acid + trehalose) were mixed in a specific ratio, and trehalose was used to replace part of the hyaluronic acid to prepare different groups of adhesive layer solutions (forming an adhesive layer after drying). The viscosity of each group was compared (average of three repetitions) using a viscometer (Brookfield DVE digital viscometer, brand: Brookfield) at a detection speed of 100%. The results are shown in Table 1.

[0099] Table 1

[0100]

[0101] The results in Table 1 show that the addition of trehalose can reduce the viscosity of the adhesive layer solution, and as the trehalose content increases, the viscosity decreases accordingly. The viscosity of Group 2 is lower than that of Group 1, which can reduce the situation where the needle tip sticks to the support part. However, compared with Group 3, it has a better viscosity and has a better effect on fixing the needle tip and the support part.

[0102] Therefore, the subsequent adhesive layer solution is selected from a formula containing both hyaluronic acid and trehalose, and the ratio of hyaluronic acid to trehalose is similar to that of Group 2 (hyaluronic acid: trehalose is 9:1) to prepare the subsequent adhesive layer solution.

[0103] 1.4. Preparation of microneedles

[0104] The adhesive layer solution (comprising 5% by weight of trehalose and 47% by weight of hyaluronic acid) is spread on the microneedle mold containing the needle tip in point 1.1, and the adhesive layer pressing device is used to apply force to the adhesive layer solution so that the adhesive layer solution fills the microneedle mold. Next, the support part prepared in point 1.2.1 is placed in the microneedle mold containing the needle tip and the adhesive layer solution, so that the adhesive layer solution adheres to the support part and the needle tip. Next, the microneedle mold containing the needle tip, the adhesive layer solution and the support part is left to stand overnight at room temperature, and then dried at 37°C for 30 minutes, and then the microneedle can be taken out of the microneedle mold and subsequent performance tests are performed. It can be understood that regardless of whether the support part is made of a sticky substance or a non-sticky substance, the subsequent performance tests show a consistent trend. In order to simplify the space, the microneedles mentioned in Example 1 below are represented by microneedles whose support part is a non-sticky substance (polylactic acid).

[0105] The height of the microneedle of Example 1 is 1200 microns, and the height of the support portion is about 600 microns, which allows the needle tip to penetrate into the dermis of the skin. The base width of each puncture unit is about 300 microns, but it is not limited to this. In principle, as long as the structural design can release PLLA MPs into the dermis, it should be included in the scope of the present invention. Secondly, the microneedle of Example 1 has 81 puncture units per square centimeter and contains 0.9 mg of active substance, but it is not limited to this.

[0106] 2. Microneedle efficacy test

[0107] 2.1. Microneedle puncture ability (visual observation)

[0108] To test the puncture effect of the microneedle of Example 1 (the adhesive layer includes trehalose distributed in hyaluronic acid), the microneedle of Example 1 (see Figure 3APart A and Part B in the figure are fixed on the microneedle applicator, where the polylactic acid microspheres in the microneedle tip are labeled with coumarin 6 fluorescence for subsequent observation. Then, the microneedle applicator is used to vertically apply the microneedle into the pig skin with a force of 7 Newtons. The microneedle is attached to the pig skin for 20 minutes to dissolve the microneedle adhesive layer, and then the patch is torn off to remove the support part.

[0109] Please refer to the results Figure 3A Part C (support part) and Part D (pigskin surface) in the figure respectively illustrate the support part and pigskin surface after the support part of the microneedle of Example 1 is removed from the pigskin. Figure 3A Part C of the figure shows that the support part can be completely removed from the pig skin. Figure 3A The fluorescent part of part D in the figure shows that after removing the supporting part, fluorescent array traces can be observed on the surface of the pig skin, indicating that the needle tip with fluorescent marker (with fluorescent marker) does have puncture ability and can be retained roughly intact in the pig skin.

[0110] In contrast, if the adhesive layer of the microneedle only contains hyaluronic acid (the adhesive layer does not contain trehalose, and the other preparation methods of the microneedle are the same as those in Example 1), instead of the adhesive layer of the microneedle containing a viscosity-reducing substance (such as trehalose) as in Example 1, when the support portion is removed, the needle tip portion is easily left on the support portion, resulting in loss of the needle tip portion, thereby reducing the efficiency of active substance delivery. For example, please refer to Figure 3B .

[0111] Figure 3B Part A and Part B in the figure respectively illustrate the situation of the support part and the surface of the pig skin after the support part of the microneedle is removed from the pig skin when the adhesive layer of the microneedle only contains hyaluronic acid. Figure 3B Part C and Part D of the embodiment 1 are the puncture results of the microneedles of Example 1 (the adhesive layer includes trehalose + hyaluronic acid). Figure 3A The same as Part C and Part D of Figure 3B Part A and Part B of the test are listed side by side to facilitate the comparison of the results.

[0112] Compare the support section after removal, Figure 3B The results of Part A and Part C show that when the microneedle is removed, the residual fluorescence of Part C (the adhesive layer contains trehalose + hyaluronic acid) is significantly lower than that of Part A (the adhesive layer contains hyaluronic acid), indicating that when the adhesive layer contains a viscosity-reducing substance (such as trehalose), the adhesion of the needle tip to the supporting part can be reduced, so that the needle tip will not be taken out when the supporting part is pulled out.

[0113] Compared with the surface of pigskin, Figure 3BThe D part (adhesive layer containing trehalose + hyaluronic acid) shows that the residual fluorescence retained on the pig skin surface is significantly lower than that in the B part (adhesive layer containing hyaluronic acid), indicating that when the adhesive layer contains a viscosity-reducing substance (such as trehalose), it can reduce the situation where the needle tip is taken out and remains on the pig skin surface. It can be seen that the microneedle of Example 1 can improve the transfer efficiency.

[0114] 2.2. Release of active substances during puncture

[0115] The microneedle of Example 1 was used to puncture porcine skin and rat skin in a similar manner to the test method of Example 2.1. The puncture site was cut into appropriate sizes after the needle tip was dissolved, embedded in a cryoembedding agent, and then sliced ​​to obtain skin tissue slices. The microneedle (MN) puncture position and the distribution of fluorescently labeled PLLAMPs in the skin tissue slices were then observed under a fluorescence microscope.

[0116] Please see the results Figure 4 It can be observed that the microneedles can successfully puncture both pig skin and rat skin, with a depth of, for example, 400 to 1000 microns, reaching the dermis, and PLLA MPs are distributed along the puncture site, indicating that the active substance at the needle tip can be successfully released from the needle tip.

[0117] 2.3. Distribution of active substances at different times

[0118] The microneedle applicator was used to vertically apply the microneedles of Example 1 to the back skin of the rats with a force of 7 Newtons. After the microneedles were attached to the rat skin for 20 minutes to dissolve the microneedle adhesive layer, the medical breathable tape was torn off to remove the support portion. At the 0th, 4th and 12th week time points, the rats were sacrificed, and the skin of the rats at the microneedle application site was removed, and the fluorescence distribution of the fluorescently labeled PLLA MPs in the rat skin was analyzed using a conjugate focus microscopy system.

[0119] Please see the results Figure 5 It can be observed that PLLA MPs are densely distributed along the puncture site when punctured. As time goes by, the number of PLLA MPs gradually degrades, indicating that the PLLA MPs at the needle tip can be gradually absorbed by the skin after being released after puncturing the skin.

[0120] 2.4. Distribution of active substances and observation of inflammatory response

[0121] After the microneedles of Example 1 were punctured into rats, the rats were sacrificed at the 4th week, the microneedle puncture area was marked and separated, and the rat skin tissue in this area was wrapped with lens paper to prevent shrinkage and deformation during the subsequent fixation process. Next, the rat skin tissue was immersed in 10% neutral formalin. After fixation for 23 hours, the rat skin tissue was taken out, rinsed with clean water, and then dehydrated, embedded, and paraffin sectioned. Next, the sections were stained with hematoxylin-eosin (H&E stain) to dye the cell nuclei blue-purple and the cytoplasm pink, so as to observe whether the microneedles caused foreign body reactions (increase in multinucleated giant cells) and inflammatory reactions. At the same time, in order to compare the differences in immune effects caused by different active substances and different dosage forms, intradermal injection (ID) was performed simultaneously into the dermis during the process, and the active substances were replaced with PBS or only hyaluronic acid as a control. Please refer to the results. Figure 6 The group that received intradermal injection of phosphate-buffered saline (PBS) was referred to as the PBS ID group, the group that received microneedle injection with hyaluronic acid (excluding PLLA MP) at the needle tip was referred to as the HA MNs group, the group that received intradermal injection of PLLA microspheres was referred to as the PLLA MPs ID group, and the group that received microneedle puncture according to Example 1 was referred to as the PLLA MP-MNs group. Figure 6 The green frame part of the first row of pictures is enlarged and displayed in the second row, representing the state of the superficial dermis (skin depth is approximately less than 500 microns). The black frame part of the first row of pictures is enlarged and displayed in the third row, representing the state of the deep dermis (skin depth is approximately greater than 500 microns).

[0122] Figure 6 The results showed that compared with the PBS ID group and the HA MNs group, the PLLA MPs distribution could be observed in the PLLA MPs ID group and the PLLA MP-MNs group where PLLA MPs were injected (circled by the green dotted circle in the dermis), and multinucleated giant cells were observed to aggregate (marked by the red arrows), indicating that the PLLA MPs ID group and the PLLA MP-MNs group, which injected PLLA MPs into the skin, would produce a more obvious foreign body reaction.

[0123] Furthermore, by comparing the PLLA MPs ID group and the PLLA MP-MNs group, it was found that compared with the PLLA MPs ID group, the PLLA MP-MNs group could alleviate the aggregation of multinucleated giant cells, reduce the occurrence of foreign body reaction, and make the inflammatory reaction milder because the PLLA MPs were more dispersed.

[0124] 2.5. Formation of collagen fibers

[0125] Following the steps and groups of Example 2.4, the sections of the puncture or injection sites determined by H&E staining in Example 2.4 were further stained with Masson's trichrome stain for connective tissue to identify the location of collagen. The results are shown in Figure 7 . Figure 7 The green frame part of the first row of pictures is enlarged and displayed in the second row, representing the state of the superficial dermis (skin depth is approximately less than 500 microns). The black frame part of the first row of pictures is enlarged and displayed in the third row, representing the state of the deep dermis (skin depth is approximately greater than 500 microns).

[0126] Figure 7 The results showed that after the injection of temporary filler hyaluronic acid (HA MNs group), it was seen that the higher density of collagen was distributed in the upper dermis (shallow layer), and the tissue looked denser, while the newly generated collagen in the PLLA MPs ID group (intradermal injection) was distributed around the PLLA MPs in the lower dermis (deep layer). Furthermore, it can be seen that the PLLA MP-MNs group has a synergistic effect brought by microneedles (MN) and PLLA MPs, and higher density collagen can be seen in both the upper and lower dermis. In addition, by comparing the PLLA MPs ID group (intradermal injection) and the PLLA MP-MNs group (microneedle puncture), which have the same active substance as PLLA MPs but use different injection methods, it can be found that the microneedles in the PLLA MP-MNs group can avoid excessive aggregation of PLLA MPs, and at the same time can better stimulate the surrounding skin cells and promote the production of collagen.

[0127] In summary, compared with intradermal injection, puncturing the skin through the microneedle of Example 1 can disperse PLLA MPs, avoid excessive aggregation of PLLA MPs, thereby avoiding excessively severe inflammatory reactions, and achieve better collagen regeneration effects.

[0128] Although the present invention has been disclosed as above in the form of implementation modes, it is not intended to limit the present invention. Those skilled in the art may make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention shall be determined by the definition of the attached claims.

[0129]

Explanation of symbols

[0130] 100: Microneedle

[0131] 100S:Puncture unit

[0132] 110: Support Department

[0133] 110S: Support unit

[0134] 110L: Support connection unit

[0135] 112: Lower surface

[0136] 114: Surface

[0137] 120: needle tip

[0138] 120S: Needle tip unit

[0139] 122: Active substances

[0140] 130: Adhesive layer

[0141] 130S: Adhesive layer unit

[0142] 132: Viscosity reducing substances

[0143] 134: Viscous material

[0144] 200: Microneedle patch

[0145] 300: Methods

[0146] S310, S320, S330, S340, S350, S360, S370, S380: Steps

[0147] H1, H2: Height

[0148] W: Width

[0149] X: X-axis

[0150] Y: Y axis

[0151] Z: Z axis.

Claims

1. A microneedle, characterized in that: Include: Support Department; a needle tip portion, disposed on the support portion, containing an active substance; and The adhesive layer is disposed between the support portion and the needle tip portion, and includes: Sticky materials; as well as A viscosity reducing substance is dispersed in the viscous material. 2 . The microneedle according to claim 1 , wherein the support portion comprises a support portion material, and the support portion material comprises an adhesive substance, a non-adhesive substance or a combination thereof.

3. The microneedle according to claim 2, wherein the viscous substance comprises hyaluronic acid, sodium polyglutamate, polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, gelatin or a combination thereof.

4. The microneedle according to claim 2, wherein the non-sticky material comprises chitosan, polylactic acid, polyglycolic acid, polycaprolactone, polyetheretherketone, polylactic acid-glycolic acid copolymer, polymethyl methacrylate, polyethylene or a combination thereof.

5. The microneedle according to claim 1, wherein the viscous material comprises hyaluronic acid, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamic acid, gelatin, water-soluble sugars or a combination thereof. The microneedle according to claim 1 , wherein the viscosity-reducing substance is a hydrophilic cosolvent.

7. The microneedle according to claim 6, wherein the viscosity-reducing substance comprises sucrose, lactose, mannitol, mannose, galactose, glucose, fructose, maltose, trehalose, polyethylene glycol or a combination thereof. 8 . The microneedle according to claim 1 , wherein the total weight of the adhesive layer is 100%, and the weight percentage of the viscosity-reducing substance in the adhesive layer is 5% to 50%. 9 . The microneedle according to claim 8 , wherein the total weight of the adhesive layer is 100%, and the weight percentage of the viscosity-reducing substance in the adhesive layer is 5% to 25%.

10. The microneedle according to claim 1, wherein the needle tip further comprises a biodegradable material, and the biodegradable material comprises hyaluronic acid, polyvinyl pyrrolidone, polyvinyl alcohol, polyglutamic acid, starch, gelatin, chitosan, carboxymethyl cellulose or a combination thereof.

11. The microneedle according to claim 1, wherein the active substance comprises hyaluronic acid, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycaprolactone, calcium hydroxide apatite, collagen, carboxymethyl cellulose, bioceramics or a combination thereof. The microneedle according to claim 1 , wherein the active substance is in the form of microspheres.

13. A microneedle patch, characterized in that: Include: The microneedle according to claim 1; and The patch is fixed to the supporting part of the microneedle.

14. A method for manufacturing a microneedle, characterized in that: Include: mixing the needle tip material, the active substance and water to obtain a needle tip solution; Filling the needle tip solution into a microneedle mold to obtain a molded needle tip solution; Drying the molded needle tip solution to obtain the needle tip; Mixing a viscous material, a viscosity reducing substance and water to obtain an adhesive layer solution; Filling the adhesive layer solution into the microneedle mold retaining the needle tip portion, so that the adhesive layer solution covers the needle tip portion, to obtain a molded adhesive layer solution; Provide support ministry; The support part is placed in the microneedle mold retaining the needle tip part and the molded adhesive layer solution, so that the molded adhesive layer solution adheres to the support part and the needle tip part; as well as The molded adhesive layer solution is dried to obtain the microneedle. 15 . The method according to claim 14 , wherein the total weight of the needle tip solution is 100%, and the weight percentage of the needle tip material in the needle tip solution is 3% to 50%.

16. The method of claim 14, wherein the needle tip material comprises a biodegradable material.

17. The method according to claim 14, wherein: The step of filling the microneedle mold with the needle tip solution comprises: Covering the needle tip solution on the microneedle mold; and Using a first needle tip pressing device to initially pressurize the needle tip solution so that the needle tip solution fills the microneedle mold to obtain the molded needle tip solution; as well as The step of drying the molded needle tip solution comprises: Drying the shaped needle tip solution for the first time to make the shaped needle tip solution initially solidified; and Using a second needle tip pressing device to perform secondary pressurization on the molded needle tip solution, so that the molded needle tip solution that has been initially solidified is further molded; as well as The further shaped needle tip solution is dried for a second time to obtain the needle tip.

18. The method according to claim 14, wherein the total weight of the adhesive layer solution is 100%, the weight percentage of the viscous material in the adhesive layer solution is 3% to 60%, and the weight percentage of the viscosity reducing substance in the adhesive layer solution is 0.15% to 30%. 19 . The method according to claim 18 , wherein the total weight of the adhesive layer solution is 100%, and the weight percentage of the viscosity-reducing substance in the adhesive layer solution is 3% to 15%.

20. The method of claim 14, wherein the viscosity reducing substance comprises sucrose, lactose, mannitol, mannose, galactose, glucose, fructose, maltose, trehalose, polyethylene glycol or a combination thereof.

21. The method according to claim 14, wherein the step of filling the adhesive layer solution into the microneedle mold retaining the needle tip portion comprises using an adhesive layer pressing device to pressurize the molded adhesive layer solution so that the molded adhesive layer solution covers the top of the needle tip portion.

22. The method according to claim 14, wherein the step of providing the support portion comprises: Mixing the support material and water to obtain a support solution; Filling the support portion solution into a support portion mold to obtain a molded support portion solution; and The shaped support solution is dried to obtain the support.

23. The method according to claim 22, wherein: The step of filling the support portion solution into the support portion mold comprises: covering the support solution on the support mold; and Using a first support part pressing device to initially pressurize the support part solution, so that the support part solution fills the support part mold, thereby obtaining the molded support part solution; as well as The step of drying the molded support solution comprises: Drying the molded support solution to make the molded support solution initially solidified; The second support part pressing device is used to perform secondary pressurization on the molded support part solution, so that the initially solidified molded support part solution is pressed on the bottom of the support part mold; Covering the support solution on the support mold again; Using the first support part pressing device to pressurize the support part solution, so that the support part solution covered again fills the support part mold and covers the compacted and molded support part solution, thereby obtaining a second molded support part solution; and The second-molding support portion solution is dried to shape the second-molding support portion solution into the support portion.

24. The method according to claim 14, wherein the step of providing the support portion comprises: placing the support material on the support mold; heating the support material so that the support material melts and fills the support mold; and The support material is cooled to obtain the support.

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