Microneedle preparation device and method of use thereof

Abstract

The application relates to the technical field of micro-needle preparation, in particular to a micro-needle preparation device and an application method thereof. The device comprises a micro-needle mold and a sealing device. The application method of the micro-needle preparation device comprises the following steps: placing the micro-needle mold into the sealing device and performing vacuumizing treatment, so that the micro-needle mold is changed from a first form into a second form and kept in the second form through the sealing device; and adding a target driving force to the micro-needle mold to add a fluid, the fluid gradually fills the micro-needle mold, and the micro-needle mold gradually recovers from the second form into the first form under the action of the fluid and air pressure. The application provides a novel micro-needle preparation device and an application method thereof which are self-venting, simple to operate and high in adaptability, not only significantly reduce the operation threshold and technical requirements, but also realize process simplification, ensure the efficiency and quality stability of micro-needle preparation (namely, improve the reliability of the micro-needle form, and reduce defects such as bubbles or notches).

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of microneedle preparation, in particular to a microneedle preparation device and an application method thereof. BACKGROUND

[0002] The microneedle is composed of a plurality of micron-sized fine needle tips connected in an array on a base, which can micro-invasively and painlessly penetrate the skin without touching blood vessels and nerves; it is essentially a cross-interface transmission platform, which can be used as a physical channel and functional interface for the delivery of drugs, energy, signals and samples; and has wide application prospects in the fields of medical devices, transdermal drugs, medical cosmetology and biosensing.

[0003] At present, as the mainstream technology for microneedle preparation, the mold method faces significant process bottlenecks in the core mold processing link. The main reason for this bottleneck is that the high viscosity and surface tension characteristics of polymer materials can easily produce bubble defects when filling the mold under normal conditions. These micron-sized bubbles can directly reduce the quality of microneedle forming. To solve this problem, the existing technology uses vacuum degassing treatment during the injection of the fluid. However, the applicant has noticed that this vacuum preparation process has at least two limitations; on the one hand, the process is severely limited by professional vacuum equipment, making microneedle preparation confined to professional manufacturing environments; on the other hand, the existing technical solution is difficult to adapt to the application needs of resource-limited scenarios, such as home, primary medical units or field work environments, etc. Traditional microneedle preparation methods are almost impossible to implement in these special situations.

[0004] The applicant believes that this technical dilemma directly limits the application range of microneedle products and seriously hinders the industrialization process of this technology.

[0005] Specifically, the following patent application discloses a secondary sampling process based on vacuum extraction (i.e., one fluid sampling before and after vacuum extraction):

[0006] For example, patent application CN202410847181.5 discloses a substrate-free ice microneedle and a preparation method thereof, which includes the following preparation steps: pretreating a metal core wrapped with a thermal insulation material, then dissolving polymer powder to form a solution, pouring the solution into a PDMS microneedle mold groove, performing vacuum extraction to remove bubbles, placing the pretreated metal core wrapped with the thermal insulation material into the bottom surface of the PDMS microneedle mold groove after the solution fills the PDMS microneedle mold groove, and finally placing both in a refrigerator to freeze and obtain an ice microneedle.

[0007] For example, patent application CN202510523020.5 discloses a method for preparing transdermal microneedles based on gallium-based liquid metal, which comprises the following steps: using a microsyringe or a pipette to suck the preheated liquid metal, quickly injecting it into a microneedle mold, and allowing the liquid metal to spread and completely cover the cavity of the needle tip in the mold; transferring the mold to a constant temperature vacuum box, and degassing under vacuum and reduced pressure; during the degassing process, the degassing temperature keeps the liquid metal in a flowing liquid state, and the vacuum is extracted to not higher than 10 Pa; continue to inject preheated gallium-based liquid metal or inject degradable polymer solution into the mold to form the base of the microneedle.

[0008] For another example, patent application CN202510283238.8 discloses a pregabalin sustained-release dissolving microneedle patch based on PLGA microspheres and its preparation method and application, which comprises the following steps: uniformly dispersing PLGA@PG microspheres in a hyaluronic acid solution, adding them to a microneedle mold, vacuumizing and centrifuging, drying the microneedles, and demolding to obtain a dissolving microneedle patch.

[0009] However, the applicant notices that the existing mold-based microneedle preparation method is relatively complex in preparation operation and puts forward very high operation requirements for the operator. Therefore, there is an urgent need for a simpler microneedle preparation method. SUMMARY

[0010] The purpose of the present application is to provide an application method of microneedle mold, which partially solves or alleviates the above-mentioned deficiencies in the prior art, and can improve the preparation efficiency and quality of microneedles. As mentioned above, the technical path adopted by the prior art is to perform vacuumizing operation during fluid injection, which has great limitations in application. In view of this, the present application develops a new type of microneedle preparation method which is self-venting, simple to operate and highly adaptable. This innovation not only simplifies the process, but also ensures the quality stability of the microneedle product, thereby expanding the application scenarios and range and meeting the actual needs of diversified application scenarios.

[0011] To solve the above-mentioned technical problems, the application specifically adopts the following technical solutions: the first aspect of the application is to provide an application method of a microneedle mold, the microneedle preparation device comprises a microneedle mold, and the microneedle mold comprises a mold and a sealing device for packaging the mold, and correspondingly, the method comprises the following steps: S301, providing the mold, the mold has at least one microneedle model space, the microneedle model space is formed by a second forming layer, and a porous network is formed in the second forming layer; S302, placing the mold in the sealing device and performing vacuumizing treatment, wherein the porous network changes from a first form to a second form, so that a pressure difference is generated between the porous network and the ambient air pressure; S303, sealing the sealing port of the sealing device, packaging the mold, so that the porous network remains in the second form; S304, unsealing and adding a fluid to the microneedle model space, which comprises: using a target driving force to gradually fill the microneedle model space with the fluid, and forming a gas zone in the needle tip area of the microneedle model space; under the influence of the pressure difference, the accumulated gas in the gas zone is absorbed by the porous network, thereby guiding the fluid to fill the gas zone; at this time, the porous network gradually recovers from the second form to the first form, and the fluid gradually forms a microneedle form.

[0012] In some embodiments, the second forming layer is connected to the first forming layer, and the material hardness of the second forming layer is less than or equal to the material hardness of the first forming layer. In some embodiments, the vacuumizing treatment has a vacuum strength of -0.005 to -0.1 Mpa, and the vacuumizing time is kept for more than 2 seconds. In some embodiments, the material of the sealing device is one or more of the following: a polymer material, a metal material, an inorganic non-metal material, and a composite material.

[0013] In some embodiments, the Shore hardness of the second forming layer is less than 35A, the first forming layer is a polymer material or a composite material, and the Shore hardness of the first forming layer is greater than or equal to 70A.

[0014] In some embodiments, the Shore hardness of the second forming layer is 35 to 90A. In some embodiments, the target driving force satisfies a first injection model, and the first injection model comprises:

[0015] ; wherein, is the capillary force of the inner surface of the microneedle model space, is the atmospheric pressure difference of the microneedle model space after being released, is the recovery stress that can be generated by the microneedle model space after being vacuumized, is the target driving force.

[0016] In some embodiments, the target driving force further satisfies a second injection model, the second injection model comprising: ;

[0017] wherein, is a time length required for fluid injection, is a viscosity of the fluid, is a needle tip angle of the microneedle model space.

[0018] In some embodiments, the fluid comprises any one of the following substances, or a combination of any at least two of the following substances: a compound, a polymer, a bioactive molecule, a regulatory factor, a cell, a cell product, a carrier. In some embodiments, the second forming layer is made of a material having gas solubility and air permeability. In some embodiments, the material having gas solubility and air permeability comprises one or more of the following: rubber, silicone, polydimethylsiloxane, polyurethane, metal organic framework composite material, poly N-isopropyl acrylamide hydrogel, polyolefin, styrene, fluororubber, acrylate rubber.

[0019] The present application also provides a microneedle preparation device, comprising: a microneedle mold, and the microneedle mold comprises: a mold comprising a plurality of microneedle model spaces provided by a plurality of second forming layers respectively, and a plurality of pore networks formed inside the second forming layers; the second forming layer is connected with the first forming layer, wherein the hardness of the second forming layer is less than or equal to the hardness of the first forming layer; wherein the plurality of pore networks change from an initial first form to a second form under the action of vacuum, so that a pressure difference is generated between the plurality of pore networks and the ambient air pressure; wherein the vacuum intensity corresponding to the second form is-0.005Mpa~ -0.1Mpa; a sealing device for packaging the mold so that the plurality of pore networks remain in the second form; wherein when a target driving force is used to gradually fill the microneedle model space with fluid, a gas zone is formed in the needle tip area of the microneedle model space; under the influence of the pressure difference, the fluid gradually displaces the accumulated gas, thereby guiding the fluid to fill the gas zone; at this time, the plurality of pore networks gradually recover from the second form to the first form.

[0020] In some embodiments, the Shore hardness of the second forming layer is less than 35A, the first forming layer is a polymer material or a composite material, and the Shore hardness of the first forming layer is greater than or equal to 70A; or the Shore hardness of the second forming layer is 35~90A.

[0021] Beneficial technical effects: Compared with the traditional microneedle mold preparation process, which requires the use of vacuum or centrifugal methods to drive liquid filling into the mold during the fluid injection stage, such as the secondary sampling process based on vacuum, the present application proposes a more gentle and efficient new method: pre-vacuuming the mold, and using the gas permeability of the material itself to achieve rapid automatic filling by relying on the pressure difference between the inside and outside when adding liquid. This innovative method significantly simplifies the operation process, avoids mechanical damage to active ingredients such as cells and exosomes during the centrifugal or vacuum process, and has the "ready-to-use" feature, which better meets the needs of rapid preparation and personalized treatment in clinical practice, providing a new solution for the application of microneedles in cell therapy and drug delivery.

[0022] In other words, the present application actually provides a single sampling process based on pre-vacuuming, which can greatly simplify the on-site preparation difficulty and alleviate the application difficulty in resource-limited scenarios.

[0023] Furthermore, the present application provides a soft and hard collaborative mold product for the pre-vacuum single sampling process. The mold product, on the one hand, through material selection and cooperation with the sealing device, and on the other hand, through the selection of vacuum treatment conditions, can provide a favorable initial environment for microneedle forming. That is, the collaborative selection of such materials and vacuum treatment conditions can effectively improve the quality of microneedle forming.

[0024] From another perspective, the present application also provides a bottom-up freezing path / mode, which helps to prepare high-quality microneedles. Specifically, the present application provides a frozen mold based on the bottom-up freezing mode, and the present application can also introduce a vacuum process to optimize the forming process of frozen microneedles. For example, before use, the microneedle model space can be subjected to vacuum treatment, and when the microneedle model space is subjected to fluid injection, the self-rebound ability of the mold is used to facilitate the high filling of the fluid into the microneedle model space, avoiding or reducing the failure of the preparation of the needle tip part of the microneedle due to insufficient liquid filling in the narrow needle tip area. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiment or prior art description. In all the drawings, similar elements or parts are generally identified by similar reference signs. In the drawings, each element or part is not necessarily drawn according to the actual proportion. Obviously, the drawings described below are some embodiments of the present application, and those skilled in the art can obtain other drawings according to these drawings without creating any inventive labor.

[0026] Figure 1Structure diagram of the freezing device in an exemplary embodiment of the present application;

[0027] Figure 2 Structure diagram of the forming area in an exemplary embodiment of the present application;

[0028] Figure 3 First diagram of the liquid surface adding state of the freezing device in an exemplary embodiment of the present application in the application process;

[0029] Figure 4 Second diagram of the liquid surface adding state of the freezing device in an exemplary embodiment of the present application in the application process;

[0030] Figure 5 Partial component diagram of the freezing device in an exemplary embodiment of the present application;

[0031] Figure 6 Structure diagram of the forming area in another exemplary embodiment of the present application;

[0032] Figure 7 Structure diagram of the needle shape in an exemplary embodiment of the present application;

[0033] Figure 8 Partial diagram of the freezing device in an exemplary embodiment of the present application;

[0034] Figure 9 Structure diagram of the heat dissipation port of the freezing device in an exemplary embodiment of the present application;

[0035] Figure 10 Structure diagram of the moving part in another exemplary embodiment of the present application;

[0036] Figure 11 Structure diagram of the moving part in another exemplary embodiment of the present application;

[0037] Figure 12 Diagram of the freezing effect of the microneedle model space in an exemplary embodiment of the present application;

[0038] Figure 13 Comparison diagram of the temperature difference in the freezing crystallization process between the prior art and the present application;

[0039] Figure 14 First structure diagram of the preparation component in an exemplary embodiment of the present application;

[0040] Figure 15 Structure diagram of the third template of the preparation component in an exemplary embodiment of the present application;

[0041] Figure 16 Structure diagram of the first template of the preparation component in an exemplary embodiment of the present application;

[0042] Figure 17 A schematic view of a second mold plate for preparing a component in an exemplary embodiment of the present application;

[0043] Figure 18 A partial enlarged view of a first mold plate for preparing a component in an exemplary embodiment of the present application;

[0044] Figure 19 A schematic view of gas flow in an exemplary embodiment of the present application;

[0045] Figure 20 A schematic view of filling effect of fluid in an exemplary embodiment of the present application;

[0046] Figure 21 A table of test results of a verification embodiment of the present application;

[0047] Figure 22 A table of test results of another verification embodiment of the present application;

[0048] Figure 23 A table of test results of another verification embodiment of the present application;

[0049] Figure 24 A schematic view of pore distribution in a formed layer in an exemplary embodiment of the present application;

[0050] Figure 25 A schematic view of a microneedle;

[0051] Figure 26 A schematic view of a microneedle provided by the present application;

[0052] Figure 27 A schematic view of deformation of a mold in a vacuum state in an exemplary embodiment of the present application;

[0053] Figure 28 Schematic views of piercing effects after the microneedles shown in Figure 26 , Figure 25 are used to pierce the skin, respectively;

[0054] Figure 29 A schematic view of a measurement range of Shore hardness.

[0055] The reference signs are identified: 2, freezing mold; 22, mold frame; 21, forming area; 211, second forming layer; 212, first forming layer; 3, moving part; 31, connecting piece; 32, holding piece; 31a, first connecting section; 31b, second connecting section; 311, limiting part; 312, guide part; 2121, microneedle model space; 41, first contact surface; 42, second contact surface; 421, concentrated conduction area; 5, freezing box; 6, refrigeration module; 61, first conduction surface; 7, special-shaped needle body; 71, main part; 72, puncture part; 82, fluid; 81, gas area; R1, first gap space; R2, second gap space; 01, first template; 011, first model; 0111, second surface; 0112, third surface; 0112a, first contact surface; 0112b, second contact surface; 012, base plate; 013, connecting space; 0131, first connecting space; 0132, second connecting space; 02, second template; 021, template opening; 022, connecting part; 03, third template; 031, isolation part; 032, drainage space; 0311, drainage groove. DETAILED DESCRIPTION

[0056] To make the objectives, technical solutions, and advantages of the embodiments of the present application clearer, the following will be combined with the accompanying drawings for a clear and complete description of the technical solutions in the embodiments of the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative work fall within the protection scope of the present application. In this document, the suffixes such as "module", "part", or "unit" used to represent elements are only for facilitating the description of the present application, and they have no specific meaning by themselves. Therefore, "module", "part", or "unit" can be mixedly used. In this document, the terms "upper", "lower", "inner", "outer", "front", "back", "one end", "the other end", and the like indicate the orientation or positional relationship shown in the drawings, and are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the device or element referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second" are only for the purpose of description, and cannot be understood as indicating or implying relative importance.

[0057] In this document, unless otherwise indicated and / or unless the context clearly dictates otherwise, the terms "mounting", "provided with", "connected" and the like are to be construed broadly, for example, "connected" can be fixed connection, can be detachable connection, or integral connection; can be mechanical connection, can be direct connection, or indirect connection through intermediate medium, can be internal connection of two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0058] As used herein, "and / or" includes any and all combinations of one or more of the associated items. As used herein, "plurality" means two or more, i.e., it includes two, three, four, five, etc. As used in this specification, the term "about", when used in reference to a particular value, typically means + / - 5% of the stated value, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, even more typically + / - 0.5% of the stated value. In this specification, certain embodiments can be disclosed in one format in terms of a range. It is to be understood that such a "range in terms of" description is used for convenience and brevity and should not be construed as a rigid limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all possible sub-ranges as well as individual numerical values within that range. For example, a description of a range 1-6 should be considered to have specifically disclosed sub-ranges like from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within that range, for example 1, 2, 3, 4, 5, and 6. The above rule applies regardless of the breadth of the range.

[0059] Elastic materials, also referred to as soft materials in this article, are materials that, after being deformed by external forces (tension, pressure, shear, etc., which in this article may be the force generated by vacuum), can completely recover their original shape and size when the external force is completely removed. "Complete recovery" means that the recovered shape of the elastic material is approximately identical to its original shape, with the difference being negligible in practical applications. In other words, elastic materials are materials with self-recovery properties. Examples of elastic materials include rubber (including natural and synthetic rubber), silicone, thermoplastic elastomers, polyurethane, etc. In this article, "vacuum" refers to a gaseous state at a pressure below approximately one atmosphere in a given space. In this article, hydrophilicity of a surface or material refers to molecules on the surface or material having polar groups that have a strong affinity for water, attracting water molecules or readily dissolving in water. Hydrophilicity manifests as the ability of surface (or surface material) molecules to form transient bonds with water through hydrogen bonds. The surface of solid materials formed by molecules with polar groups is easily wetted by water; this property is called hydrophilicity.

[0060] In this paper, the resulting bottom-up cold source transfer path (or tip-to-bottom freezing transfer path) allows the cold source to travel along... Figure 13 The cold source is transferred in the direction of the arrows shown in the right-hand diagram. For example, the cold source can be positioned below the freezing mold so that it can be gradually transferred from bottom to top. Alternatively, the cold source can be located below and from the sides of the freezing mold, meaning it can be transferred gradually inwards from the periphery of the tip. In other words, the cold source can be transferred either vertically from bottom to top or obliquely upwards, as long as the microneedles are frozen in a roughly bottom-to-top direction. Or, it simply requires ensuring that during the freezing process, the temperature of the lower end (or cold end) of the microneedle model space is lower than the temperature of the upper end (or hot end).

[0061] The cryo-microneedles of this invention can be used to deliver various live cells and biological products, such as stem cells, immune cells, peptides, nucleic acids, and probiotics, all of which can be stored, transported, and delivered via the cryo-microneedle platform. Furthermore, cryo-microneedles can resist the problem of skin pore closure to a certain extent, and can be completely removed after drug delivery, eliminating the problem of needle residue. Therefore, cryo-microneedles have significant advantages in the field of microneedling applications.

[0062] Applicants note that the preparation process of traditional frozen microneedles has great deficiencies in application: 1) low preparation efficiency and complex preparation operation, which is difficult to realize industrialization. For example, the traditional preparation process cannot prepare microneedles in batches, which will require large human and material costs in actual clinical application; 2) the structure of the frozen microneedle is relatively simple, and it is difficult to prepare a needle body with a special-shaped structure, and the applicability is relatively limited.

[0063] Embodiment one: contrary to the traditional preparation method of transferring cold source from top to bottom, the present application provides a frozen microneedle method of transferring cold source from tip to bottom (the principle of the preparation scheme is as shown in Figure 13 The frozen microneedle includes a needle body having a tip for puncture, and the needle body is connected to a moving part. Correspondingly, the method includes: using a mold method to prepare the microneedle; and the mold method provides a transfer path of transferring cold source from the tip to the bottom of the needle body to freeze form the microneedle.

[0064] Preferably, in the process of freeze forming, the temperature of the needle tip is lower than the temperature of the bottom of the needle body. Correspondingly, the needle tip is also called cold end, and the bottom of the needle body is called hot end.

[0065] Preferably, the step of using a mold method to prepare the microneedle includes: using a freezing device to prepare the microneedle, wherein the freezing device is used to provide at least one microneedle model space 2121 (as shown in Figure 2 The microneedle model space is used to assist the liquid to freeze form.

[0066] Further, in some embodiments, the method includes the steps of:

[0067] Providing a freezing device provided with a microneedle model space 2121, the opening of the microneedle model space is arranged towards the upper end of the freezing device, and the lower end of the freezing device is provided with a refrigeration module;

[0068] Adding liquid to the microneedle model space, and arranging a moving part above the microneedle model space;

[0069] Turning on the refrigeration module, so that a cold source transfer path from bottom to top is formed in the freezing device, to cause the liquid to freeze form the microneedle. Wherein, the formed microneedle is connected to the moving part and can be taken out through the moving part.

[0070] In some embodiments, the step of pre-treating the freezing device is further included.

[0071] For example, in some embodiments, the pre-treatment can be optionally vacuumizing the freezing device.

[0072] Alternatively, in some embodiments, the pre-treatment is optionally a surface pre-treatment on the microneedle model space, which is used to improve the surface hydrophilicity of the microneedle model space, so as to facilitate the liquid to fill the microneedle model space more easily.

[0073] In some embodiments, the method further comprises a step of: after the liquid is added, centrifuging or vacuumizing the freezing device, so as to facilitate the excess gas in the microneedle model space to be discharged.

[0074] In some embodiments, during the freeze forming process, the temperature at the top end of the microneedle model space is higher than the temperature at the bottom end of the microneedle model space, so the top end and the bottom end of the microneedle model space can also be referred to as the hot end and the cold end.

[0075] The following will exemplarily illustrate the bottom-up freeze forming scheme provided by the present application, and it should be understood that the scheme is only one preferred embodiment of the present application and should not be understood as a limitation on the technical scheme protected by the present application:

[0076] Correspondingly, the method comprises the steps of:

[0077] Providing a freezing device provided with a microneedle model space, the opening of the microneedle model space is arranged towards the upper end of the freezing device, and the lower end of the freezing device is provided with a refrigeration module; adding a liquid to the microneedle model space, and arranging a moving part above the microneedle model space; keeping the refrigeration module turned on, so that a bottom-up cold source transfer path is formed in the freezing device, so as to facilitate the liquid to be freeze formed to form the microneedle. The temperature at the top end of the microneedle model space is higher than the temperature at the bottom end of the microneedle model space.

[0078] Further, the preferred preparation method comprises the step of: S100, providing a freezing device, preferably, the freezing device is provided with a bottom-up cold source transfer path; wherein, referring to Figures 1-9 The freezing device comprises:

[0079] A refrigeration module 6, the refrigeration module 6 has a first conduction surface 61 for transferring a cold source, the first conduction surface 61 is provided with a concentrated conduction part 4 having a first contact surface 41 and a second contact surface 42, and the first contact surface 41 is in contact with the first conduction surface 61; a freezing mold 2, the freezing mold 2 comprises: a mold frame 22, the mold frame 22 is provided with a forming area 21, the forming area 21 is a recessed area formed by recessing inward along the surface of the mold frame, and the outer surface of the forming area 21 is in contact with the second contact surface 42; wherein, the recessed area of the forming area 21 is provided with a microneedle model space.

[0080] Preferably, the molding area 21 comprises: a second molding layer 211, a plurality of microneedle model spaces 2121 are formed on the second molding layer 211, and the edges of the second molding layer 211 extend outwardly and form a covering area with a first length H1 on the side of the molding area 21, so that the molding surface forms a first auxiliary space I above the microneedle model space 2121; a moving part 3, the moving part 3 comprises: a connecting piece 31, the connecting piece 31 has an outer shape structure adapted to the first auxiliary space I; wherein, the cold source transmission path arranged from bottom to top is as follows: a first conduction surface 61, a first contact surface 41, a second contact surface 42, an outer surface of the molding area 21, the microneedle model space;

[0081] S101, liquid (or referred to as a third raw material, which can be generally a drug solution that needs to be administered) is added to the molding area 21, so that the liquid level L of the liquid has a liquid level height higher than the microneedle model space 2121 and lower than the height of the first molding layer 212 (for example, lower than the separation line);

[0082] S102, the moving part is arranged in the molding area 21, while the liquid level height continues to be lower than the height of the first molding layer 212;

[0083] S103, the refrigeration module 6 is started to perform refrigeration; at this time, at least part of the liquid is gradually frozen and molded in the microneedle model space 2121 in sequence from bottom to top, to form a microneedle structure (or referred to as a needle body), and the remaining part of the liquid is attached to the connecting surface;

[0084] S104, the moving part is taken out to demold the microneedle structure.

[0085] In some embodiments, the frozen microneedle can be directly demolded from the frozen mold to be taken out. Alternatively, in some embodiments, the frozen microneedle can also be heated before demolding to facilitate easy demolding. For example, in some embodiments, the way to heat the frozen microneedle can be to heat the environment in the frozen device by a heating module arranged on the frozen device, or to heat the concentrated conduction part 4 or the frozen mold 2 by a heating module, so as to heat the microneedle.

[0086] For another example, in some embodiments, during the preparation of the frozen microneedle, the frozen device (or the internal environment of the frozen device) can also be pre-cooled by an external cooling method (for example, using a fan or other refrigeration means) before refrigeration by the frozen device.

[0087] Alternatively, in some embodiments, during the preparation of the frozen microneedle, the freezing device can also be externally cooled while the cooling device is cooling.

[0088] In some embodiments, the gradual freezing process of the liquid in the microneedle mold space 2121 from bottom to top includes the following steps:

[0089] At least one bubble is generated in the liquid at the bottom end of the microneedle mold space 2121 during the freezing process; at least one bubble is discharged upward along the direction from bottom to top as the liquid is gradually frozen from bottom to top. See Figure 12 As shown, the bubble generated by the needle tip portion will move upward along the direction of the arrow.

[0090] See Figure 13 As shown, Figure 13 The left and right sides of the figure show the temperature trend (or crystallization direction) of the microneedle in the conventional microneedle freezing scheme and the microneedle freezing scheme of the present application. Among them, the arrow shows the direction of the cold source, and the darker the color of the microneedle, the lower the temperature at the corresponding position (or the more forward the crystallization order). It is worth noting that the applicant found that this path of transferring the cold source from top to bottom (that is, crystallizing from top to bottom) is easy to cause the volume of the microneedle at the needle tip portion to increase, causing deformation, and thus affecting the strength and effectiveness of the microneedle. For example, during the cooling process from top to bottom, the bubble generated at the upper end is also easy to move downward under the trend of the crystallization direction, causing the volume of the needle tip portion to increase due to the accumulation of bubbles. For another example, the volume of the third raw material in the crystalline state is slightly larger than that in the liquid state under the same mass, so the crystallization process from top to bottom will cause part of the liquid to be squeezed to the lower end, causing the liquid volume at the lower end to increase, resulting in a certain degree of expansion deformation.

[0091] It is worth noting that the present application designs a conduction path for transferring the cold source from bottom to top, which can guide the liquid in the microneedle mold space to be quickly frozen from bottom to top. And during the freezing process of the liquid, a certain amount of bubbles may be generated, but through the freezing path from bottom to top, the bubbles can be guided to discharge upward along the direction from bottom to top, thereby ensuring that the needle tip portion of the microneedle has high strength, that is, the quality of the microneedle is better (in other words, the microneedle prepared by using the present application has higher precision and mechanical strength).

[0092] In some embodiments, during the freezing process, the temperature at the top end of the microneedle mold space is higher than the temperature at the bottom end of the microneedle mold space.

[0093] Preferably, in some embodiments, in S103, the microneedle model space 2121 is initially in a vacuum state. Specifically, when the microneedle model space 2121 is in a vacuum state, it is in a contracted state. At this time, when liquid is gradually added to the molding area, the liquid can gradually fill the microneedle model space. At this time, the microneedle model space will also gradually return from the contracted state to the standard state. In this embodiment, the vacuum state of the microneedle model space is more conducive to the effective filling of liquid, that is, avoiding defects such as pores and bubbles during the filling process.

[0094] See Figures 1-9 As shown, the present invention provides a cryogenic device capable of efficiently preparing cryogenic microneedles.

[0095] An exemplary embodiment of the present invention provides a refrigeration apparatus, comprising:

[0096] A freezer housing 5 has a support platform, and a refrigeration module 6 is disposed on the support platform. The refrigeration module 6 has a first conductive surface for transmitting cold energy. A centralized conductive portion 4 is disposed on the first conductive surface, and the centralized conductive portion 4 has a first contact surface 41 and a second contact surface 42. The first contact surface 41 and the first conductive surface 61 are disposed in surface contact. Preferably, the second contact surface 42 may be provided with at least one centralized conductive area 421, which is a region formed by at least a portion of the second contact surface 42 being recessed inward; for example, in some embodiments, see... Figure 5 As shown, the first contact surface 41 of the concentrated conduction section 4 is a flat surface for contacting the first conduction surface, while the second contact surface 42 has multiple recessed areas (i.e., concentrated conduction areas 421) formed therein.

[0097] The freezing mold 2 includes a mold frame 22 made from a first raw material. The mold frame 22 has forming areas 21 spaced apart from the concentrated conduction area 421. The forming areas 21 extend inward and downward along the surface of the mold frame (e.g., towards...). Figure 2 The area formed by the protrusion (in the direction indicated by the middle arrow) and the outer surface of the molding area 21 is adapted to the shape of the concentrated conduction area 421 (that is, the protruding part of the molding area can be inserted into the concentrated conduction area), so as to achieve face-to-face contact with the concentrated conduction area, so as to enable the molding area 21 to conduct cold source in a surface-wrapped manner; this surface-wrapped contact method is beneficial to improve the conduction efficiency of the cold source.

[0098] The forming area 21 comprises a second forming layer 211 made of a second raw material, a plurality of microneedle model spaces 2121 are formed on the second forming layer, and the edges of the second forming layer 211 extend outwardly and form a covering area with a first length H1 on the side of the forming area 21, so that the forming surface forms a first auxiliary space I above the microneedle model space 2121; a first forming layer 212 is arranged on the second forming layer 211, and the inner wall surface of the first forming layer 212 corresponds to form a second auxiliary space II; for example, in some embodiments, the first forming layer extends outwardly along the edges of the second forming layer by a second length H2. Preferably, the second length H2 can be less than or equal to the first length H1.

[0099] The moving part 3 comprises a connecting piece 31 having a shape structure adapted to the first auxiliary space I, and the connecting surface of the shape structure is preferably arranged as a rough surface;

[0100] When the moving part is arranged in the concentrated conduction area 421 and the third raw material is stored in the concentrated conduction area 421, when the refrigeration module 6 performs refrigeration, a part of the third raw material can fill the microneedle model space 2121 and form a microneedle structure under the action of a cold source, and another part of the third raw material can at least partially fill the first auxiliary space I to form a connecting frozen structure, and the connecting frozen structure can be attached to the rough surface.

[0101] Herein, the rough surface refers to a characteristic surface having a small peak-valley (for example, a wave distance <1mm), a microscopic geometric unevenness, and the peak-valley height difference (such as Ra, Rz parameters) can be formed by processing or naturally.

[0102] In some embodiments, the moving part further comprises a holding part holding piece 32 connected to the connecting piece, and the holding piece 32 is connected to the connecting piece 31; the holding piece can be used for connecting the introduction instrument to implement operation, or can be arranged in a shape convenient for hand or forceps holding. For example, the introduction instrument can be a medical introduction instrument or a medical introduction instrument such as a microneedle introduction instrument. Alternatively, in some embodiments, the connecting surface of the shape structure can also be arranged as a smooth surface.

[0103] Preferably, the second raw material is selected from soft materials, such as elastic materials, which facilitate high-quality and high-efficiency demolding of the product (i.e., cold microneedles), for example, the elastic properties of the soft material can reduce the damage to the needle body to a certain extent during the user demolding process. The surface of the second forming layer 211 can also be referred to as a soft contact surface. Preferably, the second raw material can be a material with a hardness between about 10A and 50A.

[0104] Preferably, in some embodiments, the width of the second auxiliary space II is greater than the width of the first auxiliary space I.

[0105] Preferably, in some embodiments, the upper portion of the forming area has a first opening, and the internal width of the forming area gradually decreases in the direction away from the first opening, for example, see Figure 2 As shown, the cross section of the forming area is a trapezoidal structure. For example, in some embodiments, the width of the concentrated conducting area 421 gradually decreases in the direction away from the second opening thereof; correspondingly, the outer surface of the forming area 21 is an expansion structure formed by the outward protrusion of the outer surface, and the expansion structure gradually decreases in the direction away from the first opening, so that the expansion structure is uniformly surrounded by the inner surface of the concentrated conducting area 421.

[0106] It is worth noting that the present embodiment provides a multi-layer structure design suitable for high-efficiency frozen microneedles, in which the forming area in the frozen mold 2 cooperates with the first and second forming layers to plan and form the first auxiliary space I and the second auxiliary space II in the forming area. Among them, the first auxiliary space I focuses on the accurate positioning of the moving part 3, and the soft material (i.e. the surface of the second forming layer 211) under the first auxiliary space is used to guide the formation of the connecting frozen structure, so that the frozen microneedle can be more closely connected with the moving part 3 through the connecting frozen structure, and the soft material of the first auxiliary space also helps better demolding of the connecting frozen structure. At the same time, the second auxiliary space is wider than the first auxiliary space, so that a certain gap space can be formed between the moving part and the wall surface of the second auxiliary space, which can allow the moving part to produce a certain degree of deviation when being clamped into the forming area.

[0107] For example, in some embodiments, see Figure 10 As shown, the moving part includes a connecting piece 31 and a holding piece 32, wherein the connecting piece 31 includes a first connecting section 31a and a second connecting section 31b. The first end of the first connecting section 31a is connected to the holding piece, and the second end is connected to the first end of the second connecting section 31b. Preferably, the width of the first connecting section 31a is greater than the width of the second connecting section 31b.

[0108] For example, in some embodiments, the width of the second connecting section 31b gradually decreases along the direction from the first end to the second end, i.e., the outer shape of the second connecting section 31b is adapted to the first auxiliary space I to achieve positioning purposes. For example, in some embodiments, the first connecting section 31a can be provided as a columnar structure, so that a certain gap is formed between the second connecting section 31b and the wall surface of the second auxiliary space II. It can be understood that, in the process of taking off the mold, the user can shake the moving part 3 to separate the surface of the mold from the forming area, i.e., through the shaking operation to demold. In this regard, the design of the parting space in the present embodiment can provide a certain operation space for the user.

[0109] Referring to Figure 4 As shown, the connecting pieces 31 of the moving part form first gap spaces R1 and second gap spaces R2 between the second forming layer 211 and the first forming layer 212, respectively. In some embodiments, the width of the second gap space R2 is greater than the width of the first gap space R1. The width of the gap space refers to the spacing between the connecting surface of the connecting piece 31 and the forming layer.

[0110] Preferably, in some embodiments, the frozen mold can also control the liquid level of the third raw material during use with the help of the first auxiliary space and the second auxiliary space. For example, in some embodiments, a separation line can be provided between the first auxiliary space and the second auxiliary space, i.e., a separation line is provided between the first forming layer and the second forming layer 211. In some embodiments, the ice structure can be formed below the separation line. Preferably, in steps S102-S103, only the first auxiliary space I is filled with liquid, while the second auxiliary space II remains unfilled. Through the layered forming space design, the amount of liquid can be controlled, and at the same time, the forming quality can be improved.

[0111] It can be understood that the application process of the frozen microneedle is to form a puncture channel on the skin of an object (such as a patient) by using the puncture property of the microneedle, and then to make the drug solution (such as the drug solution formed after the frozen microneedle is thawed) enter the skin through the puncture channel to complete the drug delivery process. Therefore, the strength and morphology of the frozen microneedle are crucial for the drug delivery process.

[0112] The split space with the soft contact surface adopted in the embodiment can make the microneedle body structure (especially the needle tip part) contact with the soft contact surface, so that even if the user shakes or moves during the mold taking process, the soft contact surface can better protect the structure and avoid damaging the needle tip. On the other hand, the split space design has the functions of fine positioning and coarse limiting, that is, it ensures that the moving part is in close contact with the bottom of the forming area, so that the bottom surface of the moving part can be in precise contact with the forming area, and it also helps to control the thickness of the connecting structure to some extent, reducing the consumption of the liquid medicine. In addition, coarse limiting can assist positioning while reserving a certain operation space for mold taking, limiting the mold taking shaking process and protecting the needle body structure.

[0113] Further, it is worth noting that the split space design proposed in the present application has significant advantages in preparing special-shaped needle bodies. That is, the soft and hard cooperative split space design is beneficial to reduce the risk of damage to the special-shaped needle body during mold taking.

[0114] Referring to Figure 6 , Figure 7 , the freezing device in the embodiment can be used to prepare special-shaped needle bodies. As Figure 7 shows the structure of a conventional needle body (left side) and a special-shaped needle body (right side), respectively. The special-shaped needle body 7 includes a main part 71 and a puncture part 72 connected to the main part 71, wherein the width of the puncture part 72 gradually decreases along the direction from the first end to the second end, that is, the second end of the puncture part 72 is used to form a needle tip structure, and the width of the first end of the puncture part is slightly larger than the width of the main part 71 to form a barb structure. For example, in some embodiments, the difference between the width of the first end of the puncture part and the width of the main part 71 is within about 0.1 millimeter (mm).

[0115] It is worth noting that when the special-shaped needle body penetrates the skin surface, the barb structure can form a certain limiting effect, thereby further ensuring that the melted liquid medicine can be efficiently absorbed by the skin, to some extent reducing the flow loss of the liquid medicine. On the other hand, the puncture part with a slightly smaller width has a certain puncture ability, and compared with the conventional needle shape (as shown in Figure 7 , the width of the needle body gradually decreases along the direction from the first end to the second end), it has higher strength, that is, the needle tip is not easily damaged during storage and access.

[0116] However, the applicant noticed that under the traditional frozen microneedle preparation process, it is impossible to realize the preparation of special-shaped needle bodies. Because the barb structure of the special-shaped needle body will cause damage during the mold taking process, resulting in its failure. And it can be understood that, from another point of view, compared with the traditional refrigeration scheme (such as the ice microneedle manufacturing device disclosed in the patent application with publication number CN119327019A), the present application adopts a completely different technical route.

[0117] Specifically, in the existing ice microneedle manufacturing device, a heat-conducting copper rod is used as a cold source transmission main force to directly provide the microneedle mold with an environment required for preparing ice microneedles. On the one hand, the utilization efficiency of the cold source is very low, and the microneedle forming speed is relatively slow and the strength is low. On the other hand, the operation of the heat-conducting copper rod as a handle is very inconvenient, and the low-temperature surface of the heat-conducting copper rod can easily cause frostbite when the user operates. In contrast, the present application forms a concentrated wrapping type refrigeration mode based on a multi-layer structure, which can improve the microneedle forming rate and quality (i.e., improve the freezing strength) in the process of efficient cold source transmission, while the handle end (such as the holding piece) of the moving part still maintains a relatively high surface problem, and the user can conveniently perform manual operation without being affected.

[0118] That is to say, the existing technology adopts an upward transmission of cold source transmission mode, but this upward transmission mode at least has the following problems: first, the size of the prepared microneedle patch is limited, and it is difficult to prepare large-size or batch microneedle patches; second, the operation is very inconvenient, and the heat-conducting copper rod needs to be moved and operated during the freezing and needle taking processes, and the heat-conducting copper rod has defects such as being large and easy to frostbite.

[0119] In contrast, the moving part 3 in the present application is preferably made of a non-metal lightweight material to improve the convenience and safety of operation.

[0120] Preferably, in some embodiments, the hardness of the first raw material is greater than the hardness of the second raw material. Preferably, in some embodiments, the first forming layer 212 is made of the second raw material. Alternatively, in some embodiments, the first forming layer 212 can also be made of the first raw material.

[0121] In some embodiments, referring to Figure 11 As shown, the connecting surface is provided with a guide part 312 corresponding to at least one microneedle model space, and the guide part is columnar or conical. Among them, the guide part 312 can play a certain guiding role on the one hand, that is, to guide the third raw material to fill the microneedle model space as soon as possible, and to reduce the generation of bubbles, and on the other hand, to save the amount of the third raw material to a certain extent.

[0122] Referring to Figure 11As shown, in some embodiments, the connecting surface comprises a second bottom surface for abutting with the first bottom surface of the forming area, and a side surface connected thereto, and a plurality of limiting portions 311 are arranged on the side surface, wherein the limiting portions 311 can be spherical or columnar protrusions protruding outward along the side surface, which can improve the adhesion between the connecting structure and the moving portion, thereby improving the success rate of mold taking.

[0123] In some embodiments, the cross section of the second forming layer 211 is arranged in a square-like shape. The "square-like shape" includes a square with chamfered corners or a square with adjacent sides connected by a circular arc, for example, a quadrilateral, such as a rectangle (the top corners of the rectangle are replaced by a circular arc structure), a square (the top corners of the square are replaced by a circular arc structure), etc. In particular, the cross section of the second forming layer 211 is arranged in a rectangle-like shape, i.e., the bottom surface and the side surface of the second forming layer are chamfered.

[0124] In some embodiments, the first conductive surface is a flat surface. In some embodiments, the concentrated conductive portion 4 is made of one or more of the following materials: metal, graphite, glass, ceramic. In some embodiments, the connecting surface is made of a hydrophilic material. In some embodiments, the moving portion is made of a heat-insulating material, wherein the heat-insulating material includes a polymer. For example, in some embodiments, the heat-insulating material can include one or more of the following: polyurethane, polyimide, polyethylene, glass wool, rock wool, polystyrene foam (such as extruded polystyrene foam board XPS).

[0125] In some embodiments, the freezing tank 5 is provided with a heat dissipation module, wherein the heat dissipation module can quickly discharge the heat generated by the guided refrigeration module outward by promoting gas convection. Alternatively, the heat dissipation module can also transfer heat to objects or media with lower temperature by direct contact. For example, in some embodiments, the heat dissipation module can be one or more of the following: air-cooled heat sink, water-cooled heat sink, heat pipe heat sink, liquid-cooled heat sink, semiconductor refrigeration heat sink. In some embodiments, the heat dissipation module can be arranged below the freezing tank, i.e., away from the side of the freezing mold. In some embodiments, the freezing device further comprises a heat dissipation portion arranged away from the first conductive surface 61, and the freezing tank 5 is provided with a heat dissipation opening. In some embodiments, the control unit connected to the refrigeration module 6 is used to control the refrigeration parameters of the refrigeration module.

[0126] In some embodiments, the freezing device further comprises a sterilization module, which can be an ultraviolet sterilization lamp arranged inside the box. In some embodiments, the freezing device is further provided with a digital adjustable temperature / timing module. In some embodiments, the refrigeration module 6 comprises one or more of the following: thermoelectric refrigeration device, liquid nitrogen refrigeration device, vapor compression refrigeration device, absorption refrigeration device, adsorption refrigeration device, vapor injection refrigeration device and magnetic refrigeration device. It can be understood that one refrigeration device can be used for refrigeration in the present embodiment. Alternatively, in other embodiments, in order to improve the refrigeration efficiency, any two or more of the above refrigeration devices can be used synchronously for combined refrigeration.

[0127] In the present application, the freezing mold 2 is designed to have a convex structure, so that it can be embedded in the concentrated conduction part 4, realize five-face lamination, and achieve high-efficiency refrigeration. Moreover, this five-face wrapping freezing mode design not only improves the cooling efficiency, but also reduces material waste and optimizes production cost.

[0128] In some embodiments, the freezing box is further provided with a lighting module. For example, in some embodiments, a lighting lamp is arranged inside the freezing box (such as inside the cover or around the box), which can be automatically turned on when the cover of the freezing box is opened, serving as a lighting function. Alternatively, it can have a control switch, which can be manually selected by the operator to turn on or off. In some embodiments, the freezing box is further provided with a sterilization module, for example, in some embodiments, the sterilization module can be an ultraviolet sterilization lamp, an ozone sterilization module or a plant extraction odor removal module, etc.

[0129] In some embodiments, the freezing box is further provided with a spraying module for spraying heat exchange medium. The heat exchange medium is used to accelerate the cooling of the environment and accelerate the ice needle forming speed. For example, in some embodiments, the heat exchange medium can be dry ice or other non-toxic gas. At normal temperature and pressure, dry ice will quickly sublimate from solid to gas, which will absorb a large amount of heat, causing the surrounding temperature to drop rapidly. In some embodiments, the freezing device can be provided with a display screen, which can be connected with the control unit. The display screen can display the working parameters of the freezing device (such as freezing working time, freezing temperature, etc.), and can also be provided with an interactive function, such as the user can touch the display screen to complete the function setting (such as starting the freezing program, turning on the freezing device, taking the mold, etc.).

[0130] The present application also provides a frozen microneedle product correspondingly prepared by the method of any one of the present application. In some embodiments, the frozen microneedle comprises a functional ingredient, which includes one or more of the following: a drug, a vaccine, a cell, a bacterium, a nano marker, a color additive. For example, in some embodiments, an additive with a special color can be added to the microneedle. For example, in some application scenarios, the application of microneedles with color can help the operator (such as a doctor) to observe the delivery of the drug. For example, in some embodiments, one or more functional ingredients can be directly added to the liquid raw material of the frozen microneedle. In some scenarios, the microneedle can be used as a physical penetration technology for transdermal drug delivery. By using functional matrix materials and carrying drugs such as antibacterial and anti-inflammatory, growth factors, hemostasis, antibacterial, anti-inflammatory, and other effects can be achieved, and the microneedle plays an important role in the whole process of wound healing.

[0131] For example, in some embodiments, a drug solution with healing effect can be used to solidify the soluble microneedle for wound healing. For another example, in some embodiments, a drug solution with antibacterial, analgesic, hemostatic, or other effects can be used to solidify the soluble microneedle for application to the wound to achieve a therapeutic effect.

[0132] Further, the present application also provides an application of the frozen microneedle in preparing a delivery material or a stimulating material.

[0133] For example, the microneedle containing functional materials can be used to deliver drugs, cells, bacteria, and other substances. For example, the microneedle can be used to prepare a transdermal drug delivery system. For another example, the microneedle can also be used as a stimulating material to stimulate biological skin and wounds. For another example, in some embodiments, the frozen microneedle provided by the present application can be used in medical and cosmetic fields (such as skin injection), infectious disease treatment, postoperative tissue regeneration, and other medical fields. It can be understood that the microneedle provided by the present application has good biocompatibility and can be used in different applications according to actual medical needs, which is not limited by the present application.

[0134] Preferably, the second raw material is an elastic raw material, so that the microneedle model space can be changed from the standard shape to the contracted shape. Specifically, during use, when the liquid is gradually added to the molding area, the liquid can gradually fill the microneedle model space. At this time, the microneedle model space will also gradually recover from the contracted shape to the standard shape. In this embodiment, the vacuum state of the microneedle model space is more conducive to the effective filling of the liquid, that is, to avoid defects such as pores and bubbles during the filling process.

[0135] The standard form refers to the initial form of the microneedle model space without external force, that is, the design form of the microneedle model space. The contracted form refers to the physical form exhibited by the contraction deformation under the action of external force (such as the suction force generated by vacuumizing).

[0136] In some embodiments, the low-pressure pretreatment of the second raw material can reduce the number of pores in the second raw material.

[0137] Preferably, the application selects a vacuum sealing method to maintain the freezing mold, and maintains the negative pressure state (that is, the vacuum state) of the mold before use.

[0138] In this embodiment, a material with excellent sealing performance, such as PE, PP, PET, PA, PVA, aluminum foil composite material, and multi-layer composite material (such as PE+PET, PE+PA), is preferably selected to wrap and seal the freezing mold to ensure the sealing and stability of long-term storage. In this embodiment, a material with a hardness of 10A-50A in a solid state is preferably selected to ensure structural stability and efficient demolding. In some embodiments, the second raw material is polydimethylsiloxane or silica gel.

[0139] Embodiment two: The application also provides an application method of a microneedle mold, the microneedle mold comprising: a mold, and a sealing device for packaging the mold, and the method comprises:

[0140] S301, providing the mold, the mold having at least one microneedle model space, the microneedle model space being formed by a second forming layer 211, and a plurality of pore networks being formed in the second forming layer 211; S302, placing the mold in the sealing device and performing vacuumizing treatment, wherein the plurality of pore networks changes from a first form to a second form to generate a pressure difference between the plurality of pore networks and the ambient air pressure; S303, sealing the sealing port of the sealing device to package the mold, so that the plurality of pore networks remains in the second form; S304, removing the sealing effect and adding a fluid to the microneedle model space, which comprises: using a target driving force to gradually fill the microneedle model space with the fluid to form a gas zone in the needle tip region of the microneedle model space; under the influence of the pressure difference, the accumulated gas in the gas zone is absorbed by the plurality of pore networks to gradually replace the accumulated gas with the fluid, thereby guiding the fluid to fill the gas zone; at this time, the plurality of pore networks gradually recovers from the second form to the first form, and the fluid gradually forms a microneedle form.

[0141] For example, in some embodiments, referring to Figure 24As shown, the mold is mainly made of aerosol and breathable polymer materials, and its interior is actually arranged to form a mesh structure, which can also be called a porous network.

[0142] In this embodiment, the mold and sealing device are sealed and preserved under vacuum conditions, so that the mold can change from the first form to the second form without excessive deformation of the overall structure of the mold.

[0143] like Figure 20 As shown, fluid 82 is injected into the microneedle model space. In the initial stage, fluid 82 cannot completely fill the microneedle model space, so a gas region 81 is formed at the top of the microneedle model space. Furthermore, on the one hand, due to the pressure difference between the internal pores of the mold (especially the second molding layer) and the external environment (such as the gas region 81), and on the other hand, the fluid 82 will also compress the gas region 81 to a certain extent under the action of gravity. Therefore, the gas in the gas region 81 will gradually diffuse into the pores, thereby realizing the replacement of the gas in the gas region 81 by the fluid 82.

[0144] It should be noted that, unlike the conventional technical approach of the prior art—that is, a two-stage sample addition approach involving vacuuming during fluid injection (such as fluid addition operations before and after vacuuming)—this invention provides a single sample addition operation with pre-vacuuming. Specifically, this invention pre-vacuums the mold separately (and uses a sealing device to preserve it under vacuum). During the microneedle molding process, only one continuous sample addition is needed in the microneedle model space to promote the natural formation of the microneedles and substrate shape by the fluid.

[0145] This pre-vacuum single-sample addition operation not only simplifies the user's preparation process, but also optimizes the preparation quality of microneedles (reducing the impact of the vacuum process on the shape of the mold, thereby optimizing the shape of the microneedles).

[0146] In this embodiment, the porous network formed by the polymer material refers to the network structure formed inside the polymer compound through processes such as foaming and cross-linking, consisting of interconnected or closed pores. The pore boundaries are supported by pillars or films formed by the bonding of polymer chain segments or branches. Its pore structure can present a two-dimensional honeycomb structure (polygonal pore planar aggregation) or a three-dimensional foam structure (polyhedral pore spatial aggregation), and the pore size distribution covers micropores (<2nm), mesopores (2-50nm), and macropores (>50nm), etc.

[0147] In some embodiments, multiple second molding layers are connected by a first molding layer (or, the second molding layers are interconnected with the first molding layer), and the material hardness of the second molding layer is less than or equal to the material hardness of the first molding layer.

[0148] In some embodiments, the vacuumizing strength (or in other words, the suction pressure) of the vacuumizing process is-0.005~-0.1Mpa, and the processing time is at least 2s, preferably the vacuumizing strength can be-0.04~-0.08Mpa, and the time is 15s~300s, to ensure the effective formation of the air pressure difference between the porous network and the environment, while avoiding excessive deformation of the second forming layer, affecting the microneedle forming.

[0149] In this embodiment, the single sample adding operation for pre-vacuumizing also provides a soft and hard combined mold structure, which on the one hand can ensure that the mold has sufficient self-rebound performance (i.e., based on the pressure difference, the fluid and air are replaced automatically, as shown in Figure 19 、 Figure 20 indicated), and on the other hand can ensure that the mold has certain shape stability during deformation (avoiding excessive deformation).

[0150] In some embodiments, the material of the sealing device is an aluminum foil composite material or a plastic material.

[0151] In some embodiments, the Shore hardness of the second forming layer is less than 35A, the first forming layer is a polymer material or a composite material, and the Shore hardness of the first forming layer is greater than or equal to 70A. In this embodiment, the selection of the material hardness helps to prevent the overall deformation of the mold, to ensure the integrity of the microneedle shape of the mold. Alternatively, in some embodiments, the Shore hardness of the second forming layer is 35~90A.

[0152] It can be understood that the mold used in this embodiment can be any one of the embodiments in Embodiment One, as can be seen from Figures 1-29 indicated, which is not limited by the present application.

[0153] In some embodiments, the target driving force satisfies a first injection model, and the first injection model includes:

[0154] ;

[0155] wherein, is the capillary force of the inner surface of the microneedle model space, is the atmospheric pressure difference of the microneedle model space after release, is the recovery stress that the microneedle model space can generate after being subjected to a vacuumizing process, is the target driving force.

[0156] It can be understood that the capillary force is related to the material properties of the micro-needle model space surface (i.e. determined by the second forming layer), the atmospheric pressure difference is determined by the vacuum treatment process, and the recovery stress is determined by the capillary force and the atmospheric pressure difference. In other words, the parameter values in the first injection model can be obtained in advance during the preparation process.

[0157] In this embodiment, the applicant notes that by reasonably selecting the material type and the vacuum degree, the filling injection of the fluid can be completed by a target driving force of a suitable size (such as the fluid can be injected into the micro-needle model space by an external force, or the fluid can be autonomously filled into the micro-needle model space).

[0158] From another perspective, the size of the target driving force is subject to the vacuum degree of the material to a certain extent.

[0159] In some embodiments, the target driving force also satisfies a second injection model, and the second injection model comprises:

[0160] ;

[0161] wherein, is the time required for fluid injection, is the viscosity of the fluid, is the needle tip angle of the micro-needle model space.

[0162] In this embodiment, in order to reasonably improve the efficiency of micro-needle preparation, the material type, the micro-needle model space, and the vacuum degree can be selected in coordination to complete the injection of the fluid within a reasonable time. It can be understood that the injection model defined in this embodiment can provide a guidance scheme for different types of micro-needle preparation. For example, taking a medicament as an example, the viscosity value thereof can be obtained by a measurement method specified in the art or from an existing database. In this regard, different types of vacuum degrees can be selected to pre-treat the mold for different types of medicaments.

[0163] In some embodiments, the second forming layer is made of a high polymer material. In some embodiments, the second forming layer is made of an elastic material. In some embodiments, the elastic material comprises one or more of the following: rubber, silicone, polydimethylsiloxane, polyurethane. In some embodiments, the fluid comprises one or more of the following substances: small molecules, high molecular substances, biological macromolecules, growth factors, cells, enzymes.

[0164] Figure 26 A micro-needle prepared by the preparation method provided by the present application is shown. Figure 25A schematic diagram of a microneedle with poor morphology (its tip is blunt) is shown. Below, the present invention demonstrates its quality optimization effect in the microneedle fabrication process through first and second verification examples:

[0165] First, the quality of microneedle forming is mainly judged comprehensively from the perspectives of microneedle defects and strength. This forming quality can be determined by the results of microscopic observations (such as...). Figure 25 , Figure 26 A schematic diagram of the microstructure of the prepared microneedles is shown, which illustrates that... Figure 26 The microneedles shown have almost no obvious defects and have relatively sharp tips, indicating good quality. The puncture effect of the microneedles after use can be comprehensively judged, and professional technicians can give evaluation results on a scale of poor or excellent. Vacuum packaging quality can be evaluated on a scale of poor or good.

[0166] See Figure 28 As shown, it illustrates the use of Figure 26 The microneedles shown Figure 25 The diagram shows the acupuncture effect created by microneedles piercing the skin. Figure 28 As shown in the middle left image, the microneedle successfully punctured the skin (it can be seen that...). Figure 26 The prepared microneedles have sharp tips and are of high quality, thus enabling them to penetrate skin pores smoothly. Figure 25 The tips of the microneedles shown are blunt, making it difficult for them to penetrate the skin.

[0167] Figure 21 The test data for the first verification example are shown. The implementation scheme adopted is as follows: the first molding material is thermoplastic polyurethane elastomer (TPU) with a Shore hardness of 70A, the second molding material is silicone with a Shore hardness of 20A, and the material of the sealing layer (i.e. the sealing device) is a composite of polyethylene terephthalate (PET) and polyethylene (PE).

[0168] This verification example uses different combinations of vacuum conditions (including vacuum intensity and vacuum processing time) to vacuum the mold and tests the microneedle forming quality under different combinations.

[0169] from Figure 21 The experimental data shown indicates that when the mold is vacuum-treated with a vacuum strength (or suction force) of -0.005 MPa for a duration of 2 seconds or more, the final microneedles formed by the mold exhibit superior quality. Figure 27 The left and right images respectively illustrate the vacuuming effects of the mold and sealing device under improper and optimal vacuuming conditions. It can be seen that by rationally selecting the materials, vacuum intensity, and time, the mold will not easily deform, thus meeting the requirements for microneedle fabrication. It should be understood that the mold is usually transparent.Figure 27 The purpose of dyeing the mold material is to distinguish the mold and the sealing device (i.e., the sealed packaging bag) so as to intuitively display the deformation effect.

[0170] Figures 22-23 The test data of the second verification example is shown, which tests different combinations of the first forming layer (corresponding to the use of hard material) and the second forming layer (corresponding to the use of soft material) under the same vacuum condition. Among them, the vacuum condition used is: the vacuum strength is-0.06Mpa, and the vacuum treatment time is 15s.

[0171] Referring to Figure 29 As shown, Shore A is selected as the unit of hardness in this embodiment, so as to appropriately describe the hardness of the material in the optional interval. That is to say, in other embodiments, Shore OO or Shore D can also be used to characterize the hardness, and the present application does not limit this. Among them, when Figures 22-23 In the "hard material hardness", the " / " means that the first forming layer (i.e., the hard material) and the second forming layer are integrally formed by using the same material, and the two are not distinguished.

[0172] From the results Figures 22-23 It can be seen from the results that the present application can provide two different embodiment schemes: scheme 1) the first forming layer and the second forming layer use different material types: for example, when the Shore hardness of the second forming layer is less than 35A, and the Shore hardness of the first forming layer is greater than or equal to 70A, the forming requirement can usually be met. Scheme 2) when the Shore hardness of the material of the second forming layer is greater than or equal to 35A, there is no need to additionally set the first forming layer with greater hardness, or the second forming layer and the first forming layer can be integrally formed by using the same type of material. Preferably, when the first forming layer and the second forming layer are integrally formed, the Shore hardness of the selected material is 35A~90A.

[0173] From another point of view, according to the above mold preparation method, the present application can also provide a microneedle mold, comprising: a plurality of microneedle model spaces 2121 provided by a plurality of second forming layers 211 respectively, and a plurality of porous networks formed in the second forming layers; a first forming layer 212 is used to connect between a plurality of second forming layers 211, wherein the hardness of the second forming layer 211 is less than the hardness of the first forming layer 212; wherein the plurality of porous networks change from an initial first form to a second form under the action of vacuum, so that a pressure difference is generated between the plurality of porous networks and the ambient air pressure; wherein the vacuum strength corresponding to the second form is-0.005Mpa~-0.1Mpa; a sealing device for packaging the mold so that the plurality of porous networks remain in the second form;

[0174] When the fluid is gradually filled into the microneedle model space by using the target driving force, a gas area is formed in the needle tip region of the microneedle model space; under the influence of the pressure difference, the accumulated gas in the gas area is absorbed by the porous network, so that the fluid gradually replaces the accumulated gas, thereby guiding the fluid to fill the gas area; at this time, the porous network gradually recovers from the second morphology to the first morphology.

[0175] In some embodiments, the Shore hardness of the second forming layer is less than 35A, and the Shore hardness of the first forming layer is greater than or equal to 70A. In some embodiments, the second forming layer is made of a material having gas solubility and air permeability. In some embodiments, the material having gas solubility and air permeability includes one or more of the following: rubber, silicone, polydimethylsiloxane, polyurethane, metal organic framework (MOFs) composite material, poly N-isopropyl acrylamide (PNIPAM) hydrogel, polyolefin, styrene, fluororubber, acrylate rubber.

[0176] In some embodiments, during the process of gradually recovering the microneedle model space from the second morphology to the first morphology, the fluid fills the microneedle model space from top to bottom step by step. In some embodiments, after the microneedle model space is subjected to vacuumizing treatment, the mold is sealed by using a sealing bag.

[0177] It should be noted that the applicant has noticed that in some scenarios, during the process of filling the fluid into the microneedle model space, there may be an air area at the top of the microneedle model space (i.e. the region for forming the needle tip), which may cause the needle tip to be difficult to form, or the air area may cause too many bubbles in the needle, thereby reducing the quality of the microneedle (such as reducing the strength). In view of this, the self-rebound ability of the elastic material in the present application can reduce the air area to some extent, or in other words, can guide the fluid to enter the microneedle model space more deeply, thereby improving the product quality of the microneedle.

[0178] In some embodiments, the mold can be prepared by using one or more materials. For example, the microneedle model space part of the mold can be prepared by using a soft material (or a material with resilience) to ensure that it can be extruded during the vacuumizing process and automatically rebound during the recovery process, thereby guiding the fluid to penetrate. Other parts of the mold, such as the parts connecting or supporting the microneedle model spaces, can be prepared by using a hard material (such as plastic). Especially when it comes to the batch preparation of frozen microneedles, this soft and hard combination preparation mode can combine the advantages of soft and hard materials, that is, it is convenient to take as a whole, and it is beneficial to the high-quality freezing molding of microneedles in a single space. In particular, the soft material is a rubber material.

[0179] In some embodiments, the fluid includes any one of the following substances, or a combination of any two or more of the following substances: compounds, macromolecules, bioactive molecules, regulatory factors, cells, cell products, carriers. For example, the fluid includes one or more of the following substances: chemical substances (i.e. compounds such as small molecule compounds, inorganic salts, organic solvents), macromolecules (such as synthetic macromolecules, natural macromolecules, biodegradable polymers), bioactive molecules (such as proteins, nucleic acids, polysaccharides and their compounds), regulatory factors (such as growth factors, cytokines, chemotactic factors, hormones, signaling molecules), enzymes (such as enzymes, coenzymes, ribozymes), cells (such as primary cells, stem cells, immune cells, engineered cells, microorganisms), cell products (such as exosomes, microvesicles, extracellular matrix, cell secretions), carriers (such as viral vectors, non-viral vectors, nanoparticles, liposomes, micelles); or the fluid is a combination of any two or more of the above substances (i.e. a mixture, a complex, a conjugate or a derivative of any of the above categories). For example, in some embodiments, the small molecule can be a synthetic or a natural extract. For example, in some embodiments, the macromolecular substance can be a soluble or insoluble macromolecule. For example, in some embodiments, the biological macromolecule can be a macromolecular protein, a polypeptide, a nucleic acid, etc.

[0180] The applicant notes that due to the particularity of the frozen microneedle - freezing, it requires a higher preparation process, especially when it needs to be prepared on site, which puts very high requirements on the user's operation level and supporting equipment. The preparation method provided by the present application can quickly and batch prepare multiple frozen microneedles, and the frozen microneedle can be stably formed (i.e. can reduce defects such as holes and gaps caused by bubbles or filling problems) under the cooperation of the bottom-up freezing mode and the vacuumizing operation, and has high quality (i.e. high reliability).

[0181] It can be understood that the frozen microneedle has unique advantages in drug delivery. Traditional injection methods often cause pain and discomfort to patients and may have the risk of infection. The frozen microneedle is small in shape and can easily penetrate the stratum corneum of the skin. By using its low-temperature characteristics, it can freeze the surrounding skin tissue in an instant, reduce nerve signal transmission, and reduce pain. At the same time, it can also carry drugs and accurately deliver drugs to specific layers of the skin, improve drug absorption efficiency, and enhance efficacy. For example, in the context of vaccination, it can make the vaccine more effectively enter the human body and activate the immune system.

[0182] In the field of cosmetics, the absorption capacity of the skin restricts the effect of many skin care products. The frozen microneedle can form a small channel on the surface of the skin without damaging the overall structure of the skin, allowing the effective ingredients in the skin care product to penetrate the skin better and play a deeper role. And low-temperature stimulation can promote blood circulation in the skin and stimulate cell vitality, which has a significant effect on improving skin texture, reducing wrinkles, brightening skin color, and improving the health status and appearance of the skin. Therefore, the frozen microneedle and the preparation method thereof in the present application can be applied in various fields such as medical treatment and cosmetics. Further, the mold in the present application can also be used for other types of microneedles, such as microneedles formed by drying, and the present application does not limit this.

[0183] Example three: see Figures 14-18 As shown in the figure, in order to realize the batch application of the frozen microneedle, the present application also provides a preparation process for preparing a batch mold.

[0184] The present application also provides a method for preparing a frozen mold using the mold preparation assembly, comprising the steps of:

[0185] S200, providing a mold preparation assembly, the mold preparation assembly comprising:

[0186] A first template 01, the first template 01 comprising: a substrate 012, a plurality of first models 011 are arranged at intervals on the substrate 012, the first models 011 are structures protruding upward along the first surface of the substrate 012, and a certain interval is formed between adjacent first models 011 to form a connecting space 013, the connecting space is formed with a first connecting space 0131 and a second connecting space 0132 in the direction away from the substrate; a plurality of microneedle models are arranged on the second surface of the first model;

[0187] A second template 02, a plurality of template openings 021 are arranged on the second template 02 corresponding to the plurality of first models 011, and the template openings 021 are connected by a connecting part 022;

[0188] A third template 03, which is provided with a plurality of drainage spaces 032 corresponding to the plurality of first models 011, and is provided with a partition 031 adjacent to the drainage spaces 032, and the lower end of the partition is provided with a drainage groove 0311 with a first height;

[0189] When the first template, the second template and the third template are sequentially fitted, the first model passes through the template opening, and the second template fills the first connecting space 0131, and the drainage groove is connected with the connecting part 022 to form a drainage port; and the wall of the partition can isolate the adjacent second connecting space 0132;

[0190] S201, assemble the first template, the second template and the third template into a state of sequentially fitting;

[0191] S202, inject a second raw material into a plurality of drainage spaces 032 respectively; wherein at least a part of the second raw material can cover the surface of the first model 011, and form a microneedle model space 2121 under the guidance of the microneedle model, a part of the second raw material can at least partially cover the surface of the connecting part 022, and another part of the second raw material can move to the drainage port and form a connection with the second raw material under the adjacent drainage space;

[0192] S203, make the second raw material keep molding at a molding temperature to form a corresponding frozen mold.

[0193] In some embodiments, the edge of the first template 01 has a raised side edge extending away from the first surface. In this embodiment, the raised side edge can accommodate the second raw material, avoiding waste of the second raw material.

[0194] In some embodiments, the method further comprises the step of: S204, vacuumizing the frozen mold to reduce the air in the microneedle model space 2121, and the microneedle model space will be deformed to a certain extent during the vacuumizing process.

[0195] Preferably, the second raw material in this embodiment is a material elastic raw material with gas solubility and air permeability, so that the microneedle model space can change from the standard form to the contracted form. Specifically, during use, when liquid is gradually added to the molding area, the liquid can gradually fill the microneedle model space. At this time, the microneedle model space will also gradually recover from the contracted form to the standard form. In this embodiment, the vacuum state of the microneedle model space is more conducive to the effective filling of the liquid, i.e. avoiding defects such as pores, bubbles, etc. during the filling process.

[0196] The standard form refers to the initial form of the microneedle model space when it is not subjected to external force, that is, the designed form of the microneedle model space. The contracted form refers to the physical form exhibited due to contraction deformation under the action of external force (such as the suction force generated by vacuumizing).

[0197] In some embodiments, before S202, the step of S205, low-pressure pretreatment is further included. In this embodiment, the low-pressure pretreatment of the second raw material can reduce the number of pores in the second raw material. Preferably, the cold mold is maintained by vacuum sealing in this embodiment, and the negative pressure state (i.e. vacuum state) is maintained before the mold is used. Preferably, the preferred setting range of the negative pressure state during storage in this embodiment is -0.005~ -0.1Mpa, and the negative pressure / vacuum treatment time is more than 2s. After unpacking, it can be directly used without additional vacuumizing step.

[0198] In this embodiment, materials with excellent sealing performance, such as PE, PP, PET, PA, PVA, aluminum foil composite material, and multi-layer composite material (such as PE+PET, PE+PA), are preferably selected to wrap and seal the cold mold to ensure the sealing performance and stability during long-term storage. In this embodiment, materials with a hardness of 10A~50A in solid state are preferably selected, which can ensure the structural stability and efficient demolding (it should be noted that the selection of materials can be adapted for different preparation needs, such as different parts or different microneedle types).

[0199] Referring to Figure 14 The application provides a preparation assembly for preparing a cold mold, which comprises a first mold plate 01, a second mold plate 02, and a third mold plate 03. Figure 12 The first model 011 is a structure protruding upward along the first surface of the base plate 012 (as indicated by the arrow in the figure), and a certain interval is formed between adjacent first models 011 to form a connecting space 013, which is formed with a first connecting space 0131 and a second connecting space 0132 in a direction away from the base plate (see Figure 16 The second surface of the first model is provided with a plurality of microneedle models (not shown in the figure); the second mold plate 02 is provided with a plurality of mold openings 021 corresponding to the plurality of first models 011, and the mold openings 021 are connected by a connecting portion 022; the third mold plate 03 is provided with a plurality of drainage spaces 032 corresponding to the plurality of first models 011, and adjacent drainage spaces 032 are provided with a separation portion 031, and the lower end of the separation portion is provided with a drainage groove 0311 with a first height.

[0200] When the first template, the second template and the third template are sequentially fitted, the first model passes through the template opening, and the second template fills the first connecting space 0131, while the drainage groove is connected with the connecting part 022 to form a drainage port; and the wall of the isolation part 031 can isolate the adjacent second connecting space 0132.

[0201] It can be understood that, in the embodiment and in other embodiments, the second mold is also a mold frame, that is, the second mold is a component of the frozen mold.

[0202] In some embodiments, the width of the first model 011 gradually decreases in the direction away from the first surface. In some embodiments, the first model 011 includes a second surface 0111 (on which the microneedle model is arranged) and a plurality of third surfaces 0112 arranged around the second surface, and the connection between any two surfaces of the first model is provided with a transition surface, which is an arc surface.

[0203] Specifically, during the mold preparation process, when the second raw material is poured into the drainage space 032, the second raw material will flow from the second surface 0111 to the third surface 0112, and the transition surface between the two surfaces can balance the flow rate of the second raw material, avoiding the flow rate changing too much when the raw material enters different areas, thereby relieving the problem of air holes and other defects in the raw material by relatively balanced flow rate. That is, the transition surface in the embodiment can reduce the problem of turbulent flow.

[0204] In some embodiments, the third surface 0112 is sequentially provided with a first contact surface 0112a and a second contact surface 0112b (see Figure 16 ) from the lower end to the upper end. Correspondingly, the oppositely arranged first contact surface forms the first connecting space 0131, and the oppositely arranged second contact surface 0112b forms the second connecting space 0132; wherein, when the second template is fitted on the first template, the side surface of the connecting part 022 is in contact with the first contact surface 0112a (in other words, the second template is embedded in the first connecting space).

[0205] In some embodiments, the lower end opening of the drainage space 032 is larger than the template opening 021, when the first template, the second template and the third template are sequentially fitted, part of the surface of the connecting portion 022 can be covered by the third template 03, and part of the surface is exposed through the drainage space 032. Wherein, the exposed edge of the connecting portion 022 will be covered by the added second raw material. In some embodiments, the edge of the substrate 012 is protruded in the direction away from the first surface to form a baffle.

[0206] In some embodiments, the second raw material is polydimethylsiloxane or silica gel.

[0207] It should be noted that, in this paper, the term "including", "containing" or any other variant thereof is intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed, or includes elements inherent to such process, method, article or device. Without more limitations, the element defined by the sentence "including a…" does not exclude the presence of other identical elements in the process, method, article or device including the element. Through the description of the above embodiments, those skilled in the art can clearly understand that the above embodiment method can be realized by software and necessary general hardware platform, of course, it can also be realized by hardware, but in many cases, the former is the better embodiment. Based on such understanding, the technical solutions of the present application can be embodied in the form of software product, which is stored in a storage medium (such as ROM / RAM, magnetic disk, optical disk), including a plurality of instructions for making a computer terminal (which can be a mobile phone, computer, server, or network equipment, etc.) execute the method described in each embodiment of the present application.

[0208] The embodiments of the present application are described above in combination with the drawings, but the present application is not limited to the above specific embodiments, and the above specific embodiments are only illustrative, not restrictive. Those skilled in the art can make many forms under the inspiration of the present application without departing from the purpose of the present application and the scope protected by the claims, which are all within the protection of the present application.

Claims

1. A method for applying a microneedle preparation device, characterized in that, The microneedle fabrication apparatus includes a microneedle mold, and the microneedle mold includes a mold and a sealing device for encapsulating the mold. Correspondingly, the method includes: S301, the mold is provided, the mold having at least one microneedle model space, the microneedle model space being formed by a second molding layer (211), and a porous network being formed within the second molding layer (211); S302, the mold is placed into the sealing device and vacuum is applied, wherein the porous network changes from a first form to a second form so that a pressure difference is generated between the porous network and the ambient air pressure. S303, the sealing port of the sealing device is sealed, and the mold is encapsulated so that the porous network is maintained in the second morphology; S304, release the seal and add fluid into the microneedle model space, including: The fluid is gradually filled into the microneedle model space by using a target driving force, forming a gas zone in the needle tip region of the microneedle model space; Under the influence of the pressure difference, the accumulated gas in the gas region is absorbed by the porous network, thereby guiding the fluid to fill the gas region; at this time, the porous network gradually returns from the second form to the first form, and the fluid gradually forms a microneedle shape.

2. The application method of the microneedle preparation device according to claim 1, characterized in that, The second molding layer is connected to the first molding layer, and the material hardness of the second molding layer is less than or equal to the material hardness of the first molding layer. And / or, the vacuum intensity of the vacuuming process is -0.005~-0.1 MPa, and the vacuuming time is maintained at more than 2 seconds; And / or, the sealing device is made of one or more of the following materials: polymer materials, metallic materials, inorganic non-metallic materials, and composite materials.

3. The application method of the microneedle preparation device according to claim 2, characterized in that, The Shore hardness of the second molding layer is less than 35A, the first molding layer is a polymer material or composite material, and the Shore hardness of the first molding layer is greater than or equal to 70A.

4. The application method of the microneedle preparation device according to claim 1, characterized in that, The Shore hardness of the second molding layer is 35~90A; And / or, the target driving force satisfies a first injection model, the first injection model including: ； in, The capillary force on the inner surface of the microneedle model space. The atmospheric pressure difference in the space of the microneedle model after release. This refers to the recovery stress that the microneedle model space can generate after being vacuumed. Driven by the goal.

5. The application method of the microneedle preparation device according to claim 4, characterized in that, The target driving force also satisfies a second injection model, which includes: ； in, The time required for fluid injection The viscosity of the fluid. The tip angle is the microneedle model space.

6. The application method of the microneedle preparation device according to claim 1, characterized in that, The fluid includes any one of the following substances, or a combination of any two of the following substances: compounds, polymers, bioactive molecules, regulatory factors, cells, cell products, and carriers.

7. The application method of the microneedle preparation device according to claim 6, characterized in that, The second molding layer is made of a material that is aerosolizable and breathable.

8. The application method of the microneedle preparation device according to claim 7, characterized in that, The material with aerosol and breathability is a rubber or metal-organic framework composite material.

9. The application method of the microneedle preparation device according to claim 7, characterized in that, The material with aerosol and breathability is silicone, polyurethane, polyolefin or styrene.

10. A microneedle preparation device, characterized in that, The microneedle fabrication device includes a microneedle mold, and the microneedle mold includes a mold, the mold including a plurality of microneedle model spaces (2121) provided by a plurality of second molding layers (211) respectively, and the interior of the second molding layers forms a porous network; the second molding layers (211) are interconnected with the first molding layer (212), wherein the hardness of the second molding layer (211) is less than or equal to the hardness of the first molding layer (212); Under vacuum, the porous network changes from an initial first state to a second state, thereby creating a pressure difference between the porous network and the ambient air pressure; wherein the vacuum intensity corresponding to the second state is -0.005 MPa to -0.1 MPa. A sealing device for encapsulating the mold so that the porous network remains in the second morphology; Specifically, when a target driving force is used to gradually fill the microneedle model space with fluid, a gas region is formed in the needle tip region of the microneedle model space; under the influence of the pressure difference, the fluid gradually replaces the accumulated gas, thereby guiding the fluid to fill the gas region; at this time, the porous network gradually recovers from the second morphology to the first morphology.

11. The microneedle preparation device according to claim 10, characterized in that, The Shore hardness of the second molding layer is less than 35A, the first molding layer is a polymer material or composite material, and the Shore hardness of the first molding layer is greater than or equal to 70A; or, the Shore hardness of the second molding layer is 35~90A.

Images