A layered microneedle forming method and a layered microneedle forming device

Abstract

In order to overcome the problem that the existing micro-needle forming scraping process has high viscosity requirement, influences micro-needle forming and material selection, the application provides a layered micro-needle forming method, comprising the following operation steps: a semi-closed cavity is arranged to cover a forming surface, the semi-closed cavity is filled with micro-needle forming liquid, the micro-needle forming liquid is immersed in the forming surface, vacuum suction is carried out on the air extraction surface of the micro-needle forming mold, the micro-needle forming liquid is introduced into the micro-needle cavity; the micro-needle forming mold and the semi-closed cavity are separated, and the micro-needle forming liquid outside the micro-needle cavity is removed. Meanwhile, the application also discloses a layered micro-needle forming device. The layered micro-needle forming method provided by the application can effectively overcome the problem that the micro-needle forming liquid does not shrink on the surface of the micro-needle forming area, and expand the viscosity application range of the micro-needle forming liquid.

Description

Technical Field

[0001] This invention belongs to the field of microneedle fabrication technology, and relates to a layered microneedle forming method and a layered microneedle forming device. Background Technology

[0002] In traditional layered microneedle fabrication, the molding liquid is introduced into the microneedle cavity of the molding mold via atomized spraying. This method has low introduction efficiency, resulting in molding liquid waste and numerous air bubbles in the molded microneedles. To address this issue, existing methods use a scraping coating technique to extrude the molding liquid into the microneedle cavity on the surface of the molding mold. However, existing scraping coating processes require limiting the viscosity of the molding liquid. When the viscosity is too low, the molding liquid has excessive fluidity on the surface of the molding mold, causing it to spread and making it difficult to meet the scraping conditions. Furthermore, since the molding mold is generally made of soft materials such as silicone resin, which has low wettability with the molding liquid, it is easy for the molding liquid to shrink and agglomerate on the surface of the molding mold. This results in some microneedle cavities not receiving molding liquid, leading to inconsistent molding liquid introduction amounts in different microneedle cavities. Consequently, the drug loading of the microneedles is insufficient, preventing them from achieving good drug efficacy. Some existing molding dies, such as the one shown in patent CN113491675A, have a substrate molding groove on the top surface of the microneedle cavity. Although this groove can limit the flow of the microneedle molding fluid to some extent, the vacuum suction process causes some of the microneedle molding fluid to enter the microneedle cavity, further reducing the amount of microneedle molding fluid in the groove. This leads to non-wetting shrinkage of the microneedle molding fluid on the bottom surface of the groove, affecting the drug loading capacity of the microneedle cavity at different locations. In addition, this groove is not suitable for the film scraping process, as microneedle molding fluid will remain at the corners of the groove, resulting in waste of the active pharmaceutical ingredient. It is also not convenient for the reuse of the molding die and continuous production, and it is easy to cause contamination at the corners.

[0003] On the other hand, since the microneedle cavity is on the micrometer scale, it is easy for air to be trapped. After coating, vacuum conditions need to be set to draw the molding liquid into the microneedle cavity. If the viscosity of the molding liquid is too high, it will also affect the efficiency of the molding liquid entering the molding cavity. Moreover, the high viscosity of the molding liquid is not conducive to the subsequent removal of air bubbles from the microneedle cavity, and air bubbles are also easy to remain. At the same time, the existing coating process also greatly limits the types of raw materials that can be selected for microneedle preparation due to the viscosity requirements of the molding liquid. A large amount of excipients need to be added to the molding liquid to increase its viscosity, which in turn affects the actual drug loading of the microneedle. Summary of the Invention

[0004] To address the problem that existing microneedle forming processes require high viscosity, which affects microneedle forming and raw material selection, this invention provides a layered microneedle forming method and a layered microneedle forming device.

[0005] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0006] On one hand, the present invention provides a layered microneedle forming method, comprising the following steps:

[0007] Microneedle Forming: The microneedle forming mold includes a forming surface and a vacuuming surface. A microneedle forming area for forming microneedles is provided on the microneedle forming mold. The microneedle forming area is made of a breathable material. Multiple microneedle cavities are provided on the surface of the forming surface of the microneedle forming area. A semi-enclosed cavity is provided to detachably cover the forming surface. The semi-enclosed cavity is filled with microneedle forming liquid. The microneedle forming liquid immerses the forming surface. Vacuuming is performed on the vacuuming surface of the microneedle forming mold to introduce the microneedle forming liquid into the microneedle cavity. The microneedle forming mold and the semi-enclosed cavity are separated, and the microneedle forming liquid outside the microneedle cavity is removed.

[0008] Substrate molding: The substrate molding liquid is applied to the molding surface of the microneedle molding mold, cured and demolded to obtain a layered microneedle including microneedles and substrate.

[0009] Optionally, the viscosity of the microneedle forming fluid at 25°C is 1.680–50000 cps.

[0010] Optionally, the semi-enclosed cavity is a groove-shaped structure with an open top, and the molding surface can detachably close the open top of the semi-enclosed cavity.

[0011] Optionally, the minimum distance between the liquid surface of the microneedle forming liquid and the forming surface is greater than 0.1 mm.

[0012] Optionally, in the "microneedle forming" operation, the forming surface of the microneedle forming mold is set downward so that the forming surface covers and closes the top opening of the semi-closed cavity. The microneedle forming mold and the semi-closed cavity are inverted so that the semi-closed cavity is above the microneedle forming mold. The microneedle forming liquid is immersed in the forming surface. The vacuum surface of the microneedle forming mold is vacuumed to allow the microneedle forming liquid to be introduced into the microneedle cavity.

[0013] Maintain vacuum suction, invert the microneedle forming mold and semi-closed cavity again, separate the microneedle forming mold and semi-closed cavity, perform a film scraping operation on the forming surface, and scrape the microneedle forming liquid outside the microneedle cavity into the semi-closed cavity.

[0014] Optionally, a sealing ring is provided on the inner edge of the top opening of the semi-enclosed cavity, and the forming surface of the microneedle forming mold abuts against the sealing ring to close the semi-enclosed cavity.

[0015] Optionally, the inner edge of the top opening of the semi-enclosed cavity is provided with a stepped groove for positioning the microneedle forming mold, and the sealing ring is located in the stepped groove.

[0016] Optionally, the microneedle forming mold includes a support plate and multiple microneedle forming areas. The shape of the microneedle forming areas is consistent with the base shape of the layered microneedles to be prepared. The multiple microneedle forming areas are embedded in the support plate at intervals. The support plate is made of rigid material, and the microneedle forming areas are made of flexible and breathable material.

[0017] Optionally, the surface air pressure of the forming surface is greater than the surface air pressure of the extraction surface.

[0018] Optionally, the "microneedle forming" operation may also include a solidification operation of the microneedle forming liquid in the microneedle cavity.

[0019] Optionally, in the "substrate forming" operation, a coating mold is used to cover the forming surface of the microneedle forming mold. The coating mold has multiple substrate forming through holes corresponding to the positions of multiple microneedle forming areas. The substrate forming liquid is applied to the surface of the coating mold, and the substrate forming liquid is scraped into and filled into the multiple substrate forming through holes by a scraper. The substrate forming liquid is then cured. The coating mold and the microneedle forming mold are separated, and the layered microneedles including microneedles and substrate are obtained by demolding.

[0020] On the other hand, the present invention provides a layered microneedle forming device, including a semi-enclosed cavity, a microneedle forming mold, and a vacuum suction device. The semi-enclosed cavity has a top opening, the microneedle forming mold includes a forming surface and a suction surface, the microneedle forming surface is provided with a microneedle forming area for forming microneedles, the microneedle forming area is made of a breathable material, and the microneedle forming area extends to the forming surface and the suction surface. The microneedle forming area has multiple microneedle cavities on the surface of the forming surface. The microneedle forming mold can be detachably closed at the top opening of the semi-enclosed cavity, and the forming surface faces the semi-enclosed cavity. The vacuum suction device is used to perform vacuum suction on the surface of the microneedle forming mold away from the semi-enclosed cavity.

[0021] The layered microneedle molding method provided by this invention employs a semi-enclosed cavity to contain the microneedle molding liquid, and simultaneously positions the semi-enclosed cavity on the molding surface of the microneedle molding mold, allowing the microneedle molding liquid to immerse the molding surface of the microneedle molding mold. This operation effectively ensures the coverage of the microneedle molding liquid by the microneedle molding liquid in the microneedle cavity, avoiding the problem of inconsistent infusion volume in each microneedle cavity due to the fluidity of the microneedle molding liquid. Furthermore, by controlling the distance between the liquid surface of the microneedle molding liquid and the molding surface, the problem of non-wetting and shrinkage of the microneedle molding liquid on the surface of the microneedle molding area is overcome. Combined with vacuum suction, this method can effectively cover the microneedle cavity with the microneedle molding liquid. The microneedle forming fluid is introduced into the microneedle cavity. After the fluid is introduced into the microneedle cavity, it is removed from the semi-enclosed cavity. The microneedle forming fluid outside the microneedle cavity is scraped off. Since the microneedle forming fluid has been introduced into the microneedle cavity, the scraping operation ensures the consistency of the amount of microneedle forming fluid in different microneedle cavities. Even microneedle forming fluids with low viscosity can be successfully filled into the microneedle cavity using this method. This effectively broadens the viscosity requirements for microneedle forming fluids, thereby also broadening the range of materials that can be selected for microneedle forming fluids, reducing the amount of excipients used for thickening, and effectively increasing the concentration of active ingredients, which is beneficial for the development of microneedle materials and the improvement of drug loading. Attached Figure Description

[0022] Figure 1 This is a schematic diagram of the structure of the semi-enclosed cavity and microneedle forming mold provided by the present invention;

[0023] Figure 2 This is a schematic diagram of the semi-enclosed cavity and microneedle forming mold provided by the present invention from another perspective;

[0024] Figure 3 This is a cross-sectional schematic diagram of the microneedle forming mold provided by the present invention;

[0025] Figure 4 This is a schematic diagram of the coating mold and microneedle forming mold provided by the present invention;

[0026] Figure 5 These are electron microscope images of the layered microneedles provided in Embodiment 1 of the present invention;

[0027] Figure 6 This is an electron microscope image of the layered microneedles provided in Comparative Example 1 of this invention.

[0028] The reference numerals in the accompanying drawings are as follows:

[0029] 1. Microneedle forming mold; 11. Air extraction surface; 12. Forming surface; 13. Microneedle forming area; 131. Microneedle cavity; 2. Semi-closed cavity; 21. Stepped groove; 22. Sealing ring; 3. Coating mold; 31. Forming through hole. Detailed Implementation

[0030] To make the technical problems solved, the technical solutions, and the beneficial effects of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0031] See Figures 1-4 As shown, an embodiment of the present invention provides a layered microneedle fabrication method, including the following steps:

[0032] Microneedle Forming: The microneedle forming mold 1 includes a forming surface 12 and a vacuuming surface 11. A microneedle forming area 13 for forming microneedles is provided on the microneedle forming mold 1. The microneedle forming area 13 is made of a breathable material. The microneedle forming area 13 is located on the surface of the forming surface 12 and has multiple microneedle cavities 131. A semi-enclosed cavity 2 is provided to detachably cover the forming surface 12. The semi-enclosed cavity 2 is filled with microneedle forming liquid, which immerses the forming surface 12. The vacuuming surface 11 of the microneedle forming mold 1 is vacuumed to allow the microneedle forming liquid to be introduced into the microneedle cavities 131. The microneedle forming mold 1 and the semi-enclosed cavity 2 are separated, and the microneedle forming liquid outside the microneedle cavities 131 is removed.

[0033] Substrate molding: The substrate molding liquid is applied to the molding surface 12 of the microneedle molding mold 1, cured and demolded to obtain a layered microneedle including microneedles and substrate.

[0034] By employing a semi-enclosed cavity 2 to contain the microneedle forming fluid, and simultaneously placing the semi-enclosed cavity 2 on the forming surface 12 of the microneedle forming mold 1, the microneedle forming fluid is submerged in the forming surface 12 of the microneedle forming mold 1. This operation method effectively ensures that the microneedle forming fluid covers the microneedle cavities 131, avoiding the problem of inconsistent introduction volume in each microneedle cavity 131 due to the fluid's own fluidity. Simultaneously, by controlling the distance between the surface of the microneedle forming fluid and the forming surface 12, the problem of non-wetting and shrinkage of the microneedle forming fluid on the surface of the microneedle forming area 13 is overcome. Combined with vacuum suction, the microneedle forming fluid can be introduced into the microneedles. In cavity 131, the microneedle forming fluid is introduced into the microneedle cavity 131 and then removed from the semi-enclosed cavity 2. The microneedle forming fluid outside the microneedle cavity 131 is scraped off. Since the microneedle forming fluid has been introduced into the microneedle cavity 131, the scraping operation ensures the consistency of the amount of microneedle forming fluid in different microneedle cavities 131. Even microneedle forming fluids with low viscosity can be successfully filled into the microneedle cavity 131 using this method, effectively broadening the viscosity requirements for microneedle forming fluids, thereby also broadening the range of materials that can be selected for microneedle forming fluids, reducing the amount of excipients used for thickening, and effectively increasing the concentration of active ingredients, which is beneficial for the development of microneedle materials and the improvement of drug loading.

[0035] In the description of this invention, the term "layered microneedles" refers to a microneedle array structure prepared using different materials for the microneedles and the substrate. Typically, the molding material for the microneedles can be a soluble material, including but not limited to acrylonitrile-butadiene-styrene copolymer (ABS), ethylene-vinyl acetate copolymer, polyvinylidene chloride, polyfluorinated olefins, perfluoroolefins, polyacrylonitrile, polyvinyl ketone, dextran, cellulose, heparin, hyaluronic acid, alginate, etc. The molding material for the substrate can be a soluble or poorly soluble material. Depending on the needs, active ingredients for pharmaceutical or cosmetic purposes can be added only to the microneedles, or active ingredients for pharmaceutical or cosmetic purposes can be added to both the microneedles and the substrate. These active ingredients can be trace amounts of active substances, DNA, RNA, pharmaceutical preparations, and vaccines.

[0036] In the preparation of layered microneedles, the microneedles and the substrate need to be processed through different steps.

[0037] In some embodiments, the viscosity of the microneedle forming fluid at 25°C is 1.680–50000 cps.

[0038] By employing the layered microneedle forming method provided by this invention, the viscosity requirements of the microneedle forming fluid can be effectively reduced, and the applicability to different microneedle forming fluids can be improved. When the viscosity of the microneedle forming fluid at 25°C is within the aforementioned range, it is suitable for preparation using the layered microneedle forming method provided by this invention. In particular, the layered microneedle forming method provided by this invention is especially suitable for low-viscosity microneedle forming fluids that are difficult to handle using conventional microneedle forming processes. Low-viscosity microneedle forming fluids refer to those with a viscosity of 1.680–1000 cps at 25°C. When using low-viscosity microneedle forming fluids, the layered microneedle forming method provided by this invention is more conducive to filling the tip of the microneedle cavity 131, resulting in a complete microneedle structure.

[0039] In different embodiments, the semi-enclosed cavity 2 can be configured with different structures. Specifically, the enclosed cavity can be a groove-shaped structure, a cylindrical structure, or an amorphous structure with an opening, etc.

[0040] In some embodiments, the excipient and active ingredient in the microneedle forming solution are prepared in a mass ratio of (1-120):1.

[0041] like Figure 1 and Figure 2 As shown, in one embodiment, the semi-enclosed cavity 2 is a groove-shaped structure with an open top, and the molding surface 12 can detachably close the top opening of the semi-enclosed cavity 2.

[0042] In some embodiments, during the “microneedle forming” operation, the forming surface 12 of the microneedle forming mold 1 is set downwards so that the forming surface 12 covers and closes the top opening of the semi-closed cavity 2. The microneedle forming mold 1 and the semi-closed cavity 2 are inverted so that the semi-closed cavity 2 is above the microneedle forming mold 1. The microneedle forming liquid is immersed in the forming surface 12. The vacuum surface 11 of the microneedle forming mold 1 is vacuumed to introduce the microneedle forming liquid into the microneedle cavity 131.

[0043] While maintaining vacuum suction, invert the microneedle forming mold 1 and the semi-closed cavity 2 again to separate the microneedle forming mold 1 and the semi-closed cavity 2. Perform a film scraping operation on the forming surface 12 to scrape the microneedle forming liquid outside the microneedle cavity 131 into the semi-closed cavity 2.

[0044] By inverting the molding mold 1 and then scraping the molding surface 12, the residual microneedle molding liquid on the mold surface can be better scraped into the semi-enclosed cavity 2 by the downward gravity of the microneedle molding liquid. This achieves the recycling of the microneedle molding liquid and effectively avoids pollution caused by residual liquid on the mold surface during repeated use, which would prevent the production process and the final product from failing to meet the relevant requirements of GMP regulations.

[0045] By inverting the semi-enclosed cavity 2, the microneedle forming fluid can flow downwards under gravity and cover the forming surface 12 of the microneedle forming mold 1. It should be noted that in other embodiments, the semi-enclosed cavity 2 may not be inverted. Specifically, the semi-enclosed cavity 2 can be tilted so that the microneedle forming fluid covers the forming surface 12; or the inversion or tilting operation can be omitted, and the semi-enclosed cavity 2 can be directly placed on the forming surface 12, and the microneedle forming fluid can be injected into the semi-enclosed cavity 2 through a pipe.

[0046] In some embodiments, during the "microneedle forming" operation, the microneedle forming mold 1 and the semi-enclosed cavity 2 can be vertically arranged, ensuring that the microneedle forming liquid can submerge the forming surface 12. Specifically, during the "film scraping operation," the microneedle forming mold 1 can also be vertically arranged, with the semi-enclosed cavity 2 placed below the microneedle forming mold 1, so that excess microneedle forming liquid can be scraped into the semi-enclosed cavity 2.

[0047] In some embodiments, a sealing ring 22 is provided on the inner edge of the top opening of the semi-enclosed cavity 2, and the sealing ring 22 is abutted by the molding surface 12 of the microneedle molding mold 1 to close the semi-enclosed cavity 2.

[0048] In some embodiments, the inner edge of the top opening of the semi-enclosed cavity 2 is provided with a stepped groove 21 for positioning the microneedle forming mold 1, and the sealing ring 22 is located in the stepped groove 21.

[0049] The stepped groove 21 is used to limit the position of the microneedle forming mold 1, ensuring that the forming surface 12 completely covers the top opening of the semi-enclosed cavity 2. The sealing ring 22 is used to ensure the fit between the top opening of the semi-enclosed cavity 2 and the edge of the forming surface 12, so as to avoid leakage of the microneedle forming fluid.

[0050] The sealing ring 22 can be selected from an elastic rubber sealing ring.

[0051] When the microneedle forming area 13 is made of a rigid material, the tip of the microneedle is prone to breakage due to stress during demolding because rigid materials are difficult to deform. This results in the microneedle not having good penetration performance, and the broken microneedle also affects the preparation of the next batch of microneedle patches. In a preferred embodiment, the microneedle forming area 13 is made of a flexible material. Compared with rigid materials, flexible materials have deformable characteristics, which is beneficial to provide an extremely gentle demolding process and can reduce the compressive stress on the microneedle cavity 131 during the demolding process. However, due to the deformability of the flexible material, shrinkage will occur during the curing process of the microneedle and the substrate, which will cause the microneedle forming area 13 to deform, which is also not conducive to the microneedle forming effect and demolding.

[0052] In a preferred embodiment, the microneedle forming mold 1 includes a support plate and a plurality of microneedle forming areas 13. The shape of the microneedle forming area 13 is consistent with the base shape of the layered microneedles to be prepared. The plurality of microneedle forming areas 13 are embedded in the support plate at intervals. The support plate is made of rigid material, and the microneedle forming area 13 is made of flexible and breathable material.

[0053] Compared to the existing technology that involves suctioning the entire molding die and then cutting it to obtain the size and shape corresponding to the microneedle patch, this embodiment sets multiple microneedle forming areas 13 with the same shape and size as the base shape of the layered microneedles on the support plate. The microneedle forming liquid in the semi-enclosed cavity 2 is drawn into the microneedle forming area 13 by the suction action of the vacuum suction device, thus avoiding the need for additional cutting steps and the waste of microneedle forming liquid.

[0054] In some embodiments, the rigid material is selected from monocrystalline silicon, stainless steel, aluminum plate, titanium plate, silicate glass, quartz glass, ceramics, polytetrafluoroethylene, polyetheretherketone (PEEK), pyridine propanesulfonate, etc., and the flexible material is selected from siloxanes.

[0055] In this embodiment, a microneedle forming mold 1 is prepared by combining flexible and rigid materials. The microneedle forming area 13 of the flexible material is fixed to the support plate of the rigid material, so that the support plate has a supporting and fixing function for the microneedle forming area 13, which is used to maintain the stability of the shape of the microneedle forming area 13. The microneedle cavity 131 provided on the microneedle forming area 13 is used for the curing and forming of microneedles. The use of flexible materials helps to reduce the stress on the microneedles during the demolding process and improve the integrity of the microneedles after demolding. At the same time, by fixing the shape of the microneedle forming area 13 by the support plate of the rigid material, deformation of the microneedle forming area 13 during the curing and shrinkage of the microneedle forming liquid can be avoided, thereby effectively improving the forming effect and demolding integrity of the microneedles.

[0056] In some embodiments, the plurality of microneedle forming regions 13 are arranged in a matrix or randomly dispersed.

[0057] In a preferred embodiment, the plurality of microneedle forming regions 13 are arranged in a matrix.

[0058] In some embodiments, the microneedle cavity 131 is a pointed cone-shaped cavity with its tip facing the interior of the microneedle forming area 13, such as a round cone, an elliptical cone, a regular polygonal cone, an irregular polygonal cone, etc.

[0059] In some embodiments, the depth of the microneedle cavity 131 is 1μm-1000μm, and the maximum diameter (i.e., the base diameter) is 5-3000μm. Meanwhile, to ensure a certain density of the microneedle array, the distance between the microneedle cavities 131 is 4μm-1000μm.

[0060] In some embodiments, the air pressure on the surface of the molding surface 12 is greater than the air pressure on the surface of the suction surface 11, and the air pressure on the surface of the suction surface 11 is less than or equal to 0.5 MPa. In a preferred embodiment, the air pressure on the surface of the suction surface 11 is less than 0.1 MPa.

[0061] Under the aforementioned vacuum conditions, it is beneficial to improve the efficiency and depth of the microneedle forming fluid entering the microneedle cavity 131.

[0062] In some embodiments, the vacuum suction time is 0.5 to 10 minutes.

[0063] In some embodiments, the minimum distance between the liquid surface of the microneedle forming fluid and the forming surface is greater than 0.1 mm.

[0064] In the description of this invention, the term "minimum distance between the surface of the microneedle forming liquid and the forming surface 12" refers to the following: when a point is selected on the surface of the microneedle forming liquid and another point is selected on the forming surface 12, the shortest distance between the two selected points is the "minimum distance between the surface of the microneedle forming liquid and the forming surface 12".

[0065] When the minimum distance between the liquid surface of the microneedle forming fluid and the forming surface is greater than 0.1 mm, the non-wetting shrinkage of the microneedle forming fluid on the surface of the microneedle forming area 13 can be effectively suppressed, ensuring the full coverage of the forming surface 12 by the microneedle forming fluid and improving the consistency of the amount of microneedle forming fluid filled in each microneedle cavity 131.

[0066] In a specific embodiment, the minimum distance between the liquid surface of the microneedle forming liquid and the forming surface can be 0.1mm, 0.5mm, 0.9mm, 1mm, 2mm, 3mm, 5mm or 8mm.

[0067] In some embodiments, the “microneedle forming” operation further includes a solidification operation of the microneedle forming liquid in the microneedle cavity 131.

[0068] In some embodiments, the curing and molding method of the microneedle forming liquid may be one or more combinations of heating curing, thermal convection drying, thermal conduction drying and / or thermal radiation drying, room temperature convection drying, room temperature static drying, low temperature convection drying, low temperature static drying, reduced pressure drying, normal pressure drying, microwave drying, chemical crosslinking, and UV curing.

[0069] In one embodiment, the microneedle molding liquid is cured by air drying at 20-25°C for 0.5-4 hours to avoid decomposition of the active ingredients in the molding liquid. Simultaneously, the air velocity is controlled within the range of 0.2-6 m / s, ensuring that the molding liquid is not blown out of the microneedle cavity 131, nor that the curing rate is reduced due to excessively low air velocity, thus affecting production efficiency.

[0070] like Figure 4 As shown, in some embodiments, in the “substrate forming” operation, a coating mold 3 is used to cover the forming surface 12 of the microneedle forming mold 1. The coating mold 3 has multiple substrate forming through holes 31 corresponding to the positions of multiple microneedle forming areas 13. The substrate forming liquid is applied to the surface of the coating mold 3, and the substrate forming liquid is scraped into and filled into the multiple substrate forming through holes 31 by a scraper. The substrate forming liquid is then cured. The coating mold 3 and the microneedle forming mold 1 are separated, and the layered microneedles including microneedles and substrate are obtained by demolding.

[0071] Another embodiment of the present invention provides a layered microneedle forming device, including a semi-enclosed cavity 2, a microneedle forming mold 1, and a vacuum suction device. The semi-enclosed cavity 2 has a top opening. The microneedle forming mold 1 includes a forming surface 12 and a suction surface 11. The microneedle forming mold 13 is provided for forming microneedles. The microneedle forming area 13 is made of a breathable material and extends to the forming surface 12 and the suction surface 11. The microneedle forming area 13 has a plurality of microneedle cavities 131 on the surface of the forming surface 12. The microneedle forming mold 1 is detachably used to close the top opening of the semi-enclosed cavity 2, and the forming surface 12 faces the semi-enclosed cavity 2. The vacuum suction device is used to perform vacuum suction on the surface of the microneedle forming mold 1 that is away from the semi-enclosed cavity 2.

[0072] In some embodiments, the layered microneedle forming device further includes a coating mold 3, which is detachably covered on the forming surface 12 of the microneedle forming mold 1. The coating mold 3 has multiple substrate forming through holes 31 at positions corresponding to multiple microneedle forming areas 13.

[0073] The present invention will be further described below through specific embodiments:

[0074] Example 1

[0075] This embodiment illustrates the layered microneedle fabrication method provided by the present invention, including the following steps:

[0076] Microneedle Forming: The microneedle forming mold includes a forming surface and a vacuuming surface. A microneedle forming area for forming microneedles is provided on the microneedle forming mold. The microneedle forming area is made of breathable material and extends to the forming surface and the vacuuming surface. The microneedle forming area has multiple microneedle cavities on the surface of the forming surface. A semi-closed cavity is provided to cover the forming surface. The semi-closed cavity is filled with microneedle forming liquid. The semi-closed cavity is a groove-shaped structure with an open top. The forming surface of the microneedle forming mold is set downward so that the forming surface covers and closes the top opening of the semi-closed cavity. The microneedle forming mold and the semi-closed cavity are inverted so that the semi-closed cavity is above the microneedle forming mold. The viscosity of the microneedle forming liquid at 25°C is 1.680 cps. The microneedle forming liquid is immersed in the forming surface. The minimum distance between the liquid surface of the microneedle forming liquid and the forming surface is 3 mm. Vacuum suction is performed on the vacuuming surface of the microneedle forming mold to introduce the microneedle forming liquid into the microneedle cavity.

[0077] Separate the microneedle forming mold and the semi-enclosed cavity, remove the microneedle forming liquid outside the microneedle cavity, and air-dry and solidify the microneedle forming liquid in the microneedle cavity;

[0078] Substrate molding: A coating mold is used to cover the molding surface of the microneedle molding mold. The coating mold has multiple substrate molding through holes corresponding to the multiple microneedle molding areas. The substrate molding liquid is applied to the surface of the coating mold. The substrate molding liquid is scraped into and filled into the multiple substrate molding through holes by a scraper. The substrate molding liquid is cured. The coating mold and the microneedle molding mold are separated. Demolding yields a layered microneedle including microneedles and substrate.

[0079] The obtained layered microneedles were observed under an electron microscope, and the resulting electron microscope images are as follows. Figure 5 As shown, the layered microneedles obtained by the layered microneedle forming method provided by the present invention have a high drug loading capacity and excellent needle morphology.

[0080] Comparative Example 1

[0081] This comparative example is used to illustrate the layered microneedle fabrication method provided by the present invention, including the following steps:

[0082] Microneedle Forming: The microneedle forming mold includes a forming surface and a vacuuming surface. A microneedle forming area for forming microneedles is provided on the microneedle forming mold. The microneedle forming area is made of a breathable material and extends to the forming surface and the vacuuming surface. The microneedle forming area has multiple microneedle cavities on the surface of the forming surface. A metal mesh is covered on the forming surface. The microneedle forming liquid is coated onto the forming surface through the metal mesh. The viscosity of the microneedle forming liquid at 25°C is 1.680 cps. A scraper is used to scrape the metal mesh to squeeze the microneedle forming liquid into the microneedle cavities. The vacuuming surface of the microneedle forming mold is vacuumed to introduce the microneedle forming liquid into the microneedle cavities.

[0083] The microneedle forming fluid in the microneedle cavity is air-dried and cured;

[0084] Substrate molding: A coating mold is used to cover the molding surface of the microneedle molding mold. The coating mold has multiple substrate molding through holes corresponding to the multiple microneedle molding areas. The substrate molding liquid is applied to the surface of the coating mold. The substrate molding liquid is scraped into and filled into the multiple substrate molding through holes by a scraper. The substrate molding liquid is cured. The coating mold and the microneedle molding mold are separated. Demolding yields a layered microneedle including microneedles and substrate.

[0085] The obtained layered microneedles were observed under an electron microscope, and the resulting electron microscope images are as follows. Figure 6 As shown, the drug loading of the layered microneedles obtained by conventional scraping operation is low, and the drug loading of different microneedles is significantly uneven.

[0086] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A layered microneedle fabrication method, characterized in that, The following steps are included: Microneedle Forming: The microneedle forming mold includes a forming surface and a vacuuming surface. A microneedle forming area for forming microneedles is provided on the mold. The microneedle forming area is made of a breathable material. Multiple microneedle cavities are provided on the surface of the forming surface within the microneedle forming area. A semi-enclosed cavity is provided and detachably covers the forming surface. The semi-enclosed cavity is a groove-shaped structure with an open top. The forming surface detachably closes the top opening of the semi-enclosed cavity. The semi-enclosed cavity is filled with a microneedle forming fluid. The viscosity of the microneedle forming fluid at 25°C is 1.680~1000. In the first step, the microneedle forming mold is positioned with its forming surface facing downwards, covering and sealing the top opening of the semi-closed cavity. The microneedle forming mold and the semi-closed cavity are then inverted, with the semi-closed cavity positioned above the microneedle forming mold. The microneedle forming liquid is immersed in the forming surface, with the minimum distance between the liquid surface and the forming surface being greater than 0.1 mm. Vacuum suction is applied to the evacuation surface of the microneedle forming mold to introduce the microneedle forming liquid into the microneedle cavity. While maintaining vacuum suction, the microneedle forming mold and the semi-closed cavity are inverted again to separate them. A scraping operation is then performed on the forming surface to scrape the microneedle forming liquid outside the microneedle cavity into the semi-closed cavity. Substrate molding: The substrate molding liquid is applied to the molding surface of the microneedle molding mold, cured and demolded to obtain a layered microneedle including microneedles and substrate.

2. The layered microneedle forming method according to claim 1, characterized in that, A sealing ring is provided on the inner edge of the top opening of the semi-enclosed cavity, and the forming surface of the microneedle forming mold abuts against the sealing ring to close the semi-enclosed cavity.

3. The layered microneedle forming method according to claim 2, characterized in that, The top opening of the semi-enclosed cavity has a stepped groove on its inner edge for positioning the microneedle forming mold, and the sealing ring is located in the stepped groove.

4. The layered microneedle forming method according to claim 1, characterized in that, The microneedle forming mold includes a support plate and multiple microneedle forming areas. The shape of the microneedle forming areas is consistent with the base shape of the layered microneedles to be prepared. The multiple microneedle forming areas are embedded in the support plate at intervals. The support plate is made of rigid material, and the microneedle forming areas are made of flexible and breathable material.

5. The layered microneedle forming method according to claim 1, characterized in that, The surface air pressure of the molding surface is greater than the surface air pressure of the extraction surface.

6. The layered microneedle forming method according to claim 1, characterized in that, The "microneedle forming" operation also includes a solidification operation of the microneedle forming liquid in the microneedle cavity.

7. The layered microneedle forming method according to claim 1, characterized in that, In the "substrate forming" operation step, a coating mold is used to cover the forming surface of the microneedle forming mold. The coating mold has multiple substrate forming through holes corresponding to the positions of multiple microneedle forming areas. The substrate forming liquid is applied to the surface of the coating mold, and the substrate forming liquid is scraped into and filled into the multiple substrate forming through holes by a scraper. The substrate forming liquid is then cured. The coating mold and the microneedle forming mold are separated, and the layered microneedles including microneedles and substrate are obtained by demolding.

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