WO2023227003A1 - 一种微针贴片的制备方法及成型模具、对位贴合装置 - Google Patents

一种微针贴片的制备方法及成型模具、对位贴合装置 Download PDF

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Publication number
WO2023227003A1
WO2023227003A1 PCT/CN2023/095919 CN2023095919W WO2023227003A1 WO 2023227003 A1 WO2023227003 A1 WO 2023227003A1 CN 2023095919 W CN2023095919 W CN 2023095919W WO 2023227003 A1 WO2023227003 A1 WO 2023227003A1
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Prior art keywords
molding
substrate
mold
area
forming mold
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PCT/CN2023/095919
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English (en)
French (fr)
Inventor
江林
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深圳青澜生物技术有限公司
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Publication of WO2023227003A1 publication Critical patent/WO2023227003A1/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C45/00—Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor
    • B29C45/17—Component parts, details or accessories; Auxiliary operations
    • B29C45/26—Moulds

Definitions

  • the invention belongs to the technical field of microneedle preparation, and specifically relates to a preparation method of a microneedle patch, a forming mold, and an alignment and laminating device.
  • microneedle As a new type of transdermal drug delivery technology, microneedle consists of multiple micron-sized tiny needle tips connected to a base in an array.
  • the needle body is generally 10-2000 microns high and 10-50 microns wide, and can be directed through
  • the stratum corneum creates micron-sized mechanical channels to place drugs directly on the epidermis or upper dermis. It can participate in microcirculation and exert pharmacological reactions without passing through the stratum corneum. It can also be basically painless and minimally invasive, convenient and safe. Application scenarios widely.
  • microneedle products have broad development prospects, issues such as industrialization, dosage, and production process quality standards still need to be solved.
  • microneedles are mainly divided into solid microneedles, coated microneedles, soluble microneedles and hollow microneedles in terms of delivery methods.
  • the soluble microneedles are made of biodegradable polymer materials loaded with active pharmaceutical ingredients. After penetrating the stratum corneum of the skin, the functional pharmaceutical ingredients contained on the needle body will be released together with the dissolution of the soluble microneedles. , allowing drug molecules to physically penetrate the stratum corneum barrier, thereby achieving penetration and absorption of drugs into subcutaneous tissue and the human body.
  • This method of drug delivery does not require removing the needle after inserting the needle like other microneedles.
  • Dissolvable microneedles only need to be removed after drug administration. It is non-invasive, safe and efficient for patients. Compliance is good, so it has become mainstream in the market.
  • the preparation process of soluble microneedles mainly uses mold injection.
  • the specific preparation process is to inject corresponding drugs and adjuvants into the mold. After drying, solidification and shaping, the prepared microneedles can be collected from the mold. Mold injection technology can control the characteristics of microneedles, such as shape, size, array density, etc., by controlling the mold. This method is simple and easy to implement and can be carried out in general laboratories. However, the shortcomings of this method are also very prominent when expanding production. There are specific problems in the following aspects:
  • the molding mold is made of rigid material, since the rigid material is difficult to deform, the tips of the microneedles are susceptible to stress and break during demolding, resulting in the microneedles not having good penetration performance, and at the same time, the broken microneedles Needles affect the preparation of the next batch of microneedle patches; using silica gel as the mold can reduce the stress during demoulding. Therefore, existing molding molds are mostly made of materials with low mechanical strength such as silica gel.
  • silicone is prone to deformation during use, which affects the precise positioning of subsequent molding liquid injection steps and subsequent lamination steps.
  • its base will produce a certain shrinkage, which will cause the mold to Deformation affects the microneedle molding effect and is not conducive to demolding.
  • microneedle preparation process uses manual injection of the molding liquid into the molding mold individually or in a single line, and then scrapes the coating. This method is inefficient and is not suitable for the industrial production of microneedle patches.
  • the present invention provides a forming mold, an alignment and laminating device and a method for preparing microneedle patches.
  • the present invention provides a method for preparing a microneedle patch, which includes the following steps:
  • the molding mold is filled with molding liquid.
  • the molding mold includes a frame structure and a molding surface embedded in the frame structure.
  • the frame structure is a rigid material, and the molding surface is a flexible material.
  • the molding surface is provided with Multiple microneedle cavities are used for the molding of microneedles.
  • the molding liquid is introduced into the molding surface and the microneedle cavity.
  • the molding liquid is solidified and formed to obtain a substrate and multiple microneedles connected to the substrate. A portion of the substrate is obtained. The side is exposed on the surface of the forming mold;
  • the base film carries the base and the microneedles and is ejected from the mold to obtain a microneedle patch.
  • the rigid material is selected from single crystal silicon, stainless steel, aluminum plate, titanium plate, silicate glass, quartz glass, ceramic, polytetrafluoroethylene, polyether ether ketone or propane sulfonate pyridinium salt.
  • the number of the molding surfaces is multiple, and the plurality of molding surfaces are arranged at intervals on the frame structure.
  • the frame structure is provided with a plurality of molding holes, the molding surface is located on the bottom surface of the molding hole, the molding hole is closed by the molding surface to form a molding cavity, and the molding cavity is used for the base of molding.
  • the forming mold also includes a flexible plate located at the bottom of the frame structure. part and is integrally formed with the molding surface.
  • the forming mold further includes a coating plate, the coating plate is detachably provided on the frame structure, and there are holes on the coating plate at positions corresponding to the plurality of molding surfaces. A plurality of through holes closed by the molding surface to form a molding cavity.
  • the molding liquid when filling the molding liquid, the molding liquid is introduced into the molding mold, and the molding liquid is extruded and filled into multiple molding cavities through a scraper.
  • the molding surface is an air-permeable and liquid-impermeable structure.
  • the bottom of the molding surface is evacuated to discharge the gas in the microneedle cavity and introduce the molding liquid into the microneedle cavity.
  • the "alignment and attachment of the substrate film with a sticky surface to the forming mold” includes the following operations:
  • the control unit receives the position information of the forming mold and at the same time transmits the operation information to the alignment unit, and the alignment unit adjusts the forming mold to a preset position in the first area;
  • the substrate diaphragm with the substrate film is placed in the second area, the position information of the substrate diaphragm in the second area is identified through the second positioning unit, and the position of the substrate diaphragm is Information is transmitted to the control unit;
  • the control unit receives the position information of the substrate diaphragm and at the same time transmits the operation information to the alignment unit, and the alignment unit adjusts the substrate diaphragm to a preset position in the second area;
  • the alignment unit transfers the forming mold and substrate film to the lamination area for alignment and overlap;
  • the pressing unit presses the forming mold and the substrate film, and the substrate film is bonded to the base.
  • the present invention provides a molding mold, which includes a frame structure and a molding surface embedded in the frame structure.
  • the frame structure is a rigid material
  • the molding surface is a flexible material
  • the molding surface is provided with
  • the number of the molding surfaces is multiple, and the plurality of molding surfaces are arranged at intervals on the frame structure.
  • the frame structure is provided with a plurality of molding holes, the molding surface is located on the bottom surface of the molding hole, the molding hole is closed by the molding surface to form a molding cavity, and the molding cavity is used for the base of molding.
  • the forming mold further includes a flexible plate located at the bottom of the frame structure and integrally formed with the forming surface.
  • the forming mold further includes a coating plate, the coating plate is detachably provided on the frame structure, and there are holes on the coating plate at positions corresponding to the plurality of molding surfaces. A through hole, which is closed by the molding surface to form a molding cavity.
  • an alignment and laminating device including:
  • the operating area is provided with a first area for the forming mold to be placed and a second area for the substrate diaphragm to be placed;
  • a first positioning unit arranged in the first area, used to identify the position information of the forming mold in the first area, and transmit the position information of the forming mold to the control unit;
  • a second positioning unit is provided in the second area.
  • the second positioning unit is used to identify the position information of the substrate diaphragm in the second area and transmit the position information of the substrate diaphragm to the control unit. unit;
  • a control unit configured to receive the position information of the forming mold and the position information of the substrate diaphragm, and at the same time transmit operation information to the alignment unit;
  • An alignment unit is used to receive operation information from the control unit, move the mold to a preset position, move the substrate diaphragm to a preset position, and align the mold and the substrate diaphragm. overlapping;
  • the laminating unit is used to laminate the overlapping molding mold and the substrate film to bond the substrate film to the substrate.
  • the operation area also includes a laminating area for positioning and attaching the mold and the substrate film, and the positioning unit can be configured in the first area, the second area and the attaching area. move freely within the combined area.
  • the first positioning unit and the second positioning unit are selected from a visual alignment device, an ultrasonic positioning device or an infrared positioning device.
  • the first area is provided with a first conveying device for supplying the forming mold
  • the second area is provided with a second conveying device for supplying the substrate film.
  • the alignment unit includes a first manipulator and a second manipulator, the first manipulator is used to move the forming mold, and the second manipulator is used to move the substrate film.
  • the pressing unit is selected from a roller device and a pressing device.
  • the preparation method of the microneedle patch provided by the present invention, by filling the molding liquid into the molding mold, To form a base and connect multiple microneedles on the base, a flexible material and a rigid material are combined to prepare a molding mold.
  • the molding surface is a flexible material.
  • the flexible material has deformable characteristics, which beneficially provides extremely
  • the gentle demoulding process can reduce the squeezing stress of the microneedle cavity during the microneedle demoulding process.
  • the frame structure has a greater impact on the molding surface.
  • It has the function of supporting and fixing, and is used to maintain the stability of the shape of the molding surface, which can prevent the molding surface from deforming during the solidification and shrinkage process of the molding liquid, thereby effectively improving the molding effect and demoulding integrity of the microneedle, and at the same time It is also helpful to improve the alignment accuracy of subsequent substrate diaphragms.
  • the external substrate film is adhered to the substrate, and the substrate and microneedles are taken out of the mold by the substrate film, which is beneficial to ensuring the consistency of the microneedle extraction direction. , thereby avoiding the breakage problem of microneedles caused by uneven force.
  • Figure 1 is a schematic structural diagram of the forming mold provided by the present invention.
  • Figure 2 is a schematic structural diagram of another implementation of the forming mold provided by the present invention.
  • Figure 3 is a schematic structural diagram of another implementation of the forming mold provided by the present invention.
  • Figure 4 is a schematic cross-sectional view of the forming mold provided by the present invention.
  • Figure 5 is a schematic structural diagram of an alignment and laminating device provided by an embodiment of the present invention.
  • Figure 6 is a schematic structural diagram of an alignment and laminating device provided by another embodiment of the present invention.
  • Figure 7 is a schematic structural diagram of an alignment and laminating device provided by another embodiment of the present invention from another perspective;
  • Figure 8 is a schematic structural diagram of the microneedle patch provided by the present invention.
  • the invention provides a method for preparing a microneedle patch, which includes the following steps:
  • the molding mold 1 is filled with molding liquid.
  • the molding mold 1 includes a frame structure 12 and a molding surface 111 embedded in the frame structure 12.
  • the frame structure 12 is a rigid material
  • the molding surface 111 is a flexible material.
  • a plurality of microneedle cavities 1111 are provided on the molding surface 111.
  • the microneedle cavities 1111 are used for molding the microneedles 3.
  • the molding liquid is introduced into the molding surface 111 and the microneedle cavities 1111, and the molding liquid is solidified and formed to obtain the substrate 4.
  • a plurality of microneedles 3 connected to the base 4, one side of the base 4 is exposed on the surface of the mold 1;
  • the substrate film 5 carries the substrate 4 and the microneedles 3 and is ejected from the mold 1 to obtain a microneedle patch.
  • the structure of the microneedle patch is shown in Figure 8 .
  • the molding liquid is filled into the molding mold 1 to form a base 4 and a plurality of microneedles 3 connected to the base 4.
  • the molding mold 1 is prepared by combining flexible materials and rigid materials.
  • the molding surface 111 is a flexible material, which is relatively rigid. Material, the flexible material has deformable characteristics, which beneficially provides an extremely gentle demoulding process, which can reduce the extrusion stress of the microneedle cavity 1111 during the demoulding process of the microneedle 3, by fixing the molding surface 111 of the flexible material On the frame structure 12 of rigid material, the frame structure 12 has a supporting and fixing effect on the molding surface 111, which is used to maintain the stability of the shape of the molding surface 111 and avoid the molding surface 111 in the molding liquid. The deformation occurs during the curing and shrinkage process, thereby effectively improving the molding effect and demoulding integrity of the microneedles 3, and also helping to improve the alignment accuracy of the subsequent substrate diaphragm 5.
  • the outer substrate film 5 adheres to the substrate 4, and the substrate 4 and microneedles 3 are taken out of the mold 1 by the substrate film 5, which is beneficial to Ensure the consistency of the protrusion direction of the microneedle 3, thereby avoiding the breakage problem of the microneedle 3 caused by uneven force.
  • the rigid material includes, but is not limited to, single crystal silicon, stainless steel, aluminum plate, titanium plate, silicate glass, quartz glass, ceramic, polytetrafluoroethylene, polyether ether ketone (PEEK), propane sulfonate Pyridinium salt, etc.
  • the aluminum plate can be formed through electroplating or anodizing treatment
  • the flexible material is selected from siloxane.
  • the number of the molding surfaces 111 is multiple.
  • the molding surfaces 111 are spaced apart on the frame structure 12 .
  • the forming mold 1 can be implemented with different structures, specifically:
  • the frame structure 12 is provided with a plurality of molding holes 112 , the molding surface 111 is located at the bottom surface of the molding hole 112 , and the molding hole 112 is formed by the molding surface. 111 is closed to form a molding cavity 11 which is used for the molding of the substrate 4 .
  • the forming mold 1 further includes a flexible plate 14 , which is located at the bottom of the frame structure 12 and integrally formed with the forming surface 111 .
  • the forming mold 1 further includes a coating plate 13, the coating plate 13 is detachably provided on the frame structure 12, and the coating plate 13 A plurality of through holes 113 are opened on the base plate at positions corresponding to the plurality of molding surfaces 111 .
  • the through holes 113 are closed by the molding surfaces 111 to form a molding cavity 11 .
  • the molding cavity 11 is used for molding the base 4 .
  • the microneedle molding liquid is accurately injected into the corresponding position of the molding mold 1 through the coating plate 13 instead of directly injecting it at the position marked on the molding mold 1 in the prior art.
  • the method provided by this embodiment reduces the number of The impact of deformation on the accuracy of the injection position during the use of the mold.
  • the molding liquid is injected in batches through the coating plate, which improves the coating efficiency.
  • the molding cavity 11 As a cavity for receiving the molding liquid, it has the function of retaining part of the molding liquid. During the subsequent bubble removal operation, the molding liquid in the molding cavity 11 enters the microneedle cavity 1111 for replenishment. At the same time, the molding cavity 11 also The molded shape of the base 4 is limited.
  • the horizontal section of the molding cavity 11 is a rectangle, an ellipse, or any other shape.
  • the depth of the molding cavity 11 is 0.01cm-0.2cm.
  • the depth of the molding cavity 11 is related to the thickness of the substrate 4.
  • the depth of the molding cavity 11 can be set corresponding to the required thickness of the substrate 4. Specifically, since the substrate film 5 is used in this preparation method to adhere The substrate 4, therefore, is mainly provided with the necessary mechanical strength by the substrate film 5 during subsequent use, and the thickness of the substrate 4 can be reduced accordingly to reduce material costs.
  • the plurality of molding cavities 11 are arranged in a matrix or randomly dispersed.
  • a plurality of the molding cavities 11 are arranged in a matrix, and two adjacent molding cavities 11 are equidistantly spaced to facilitate the subsequent alignment operation when the substrate film 5 is pressed and pasted.
  • the microneedle cavity 1111 is a pointed cone-shaped cavity with the tip facing the inside of the molding surface 111, such as a conical cone, an elliptical cone, a regular polygonal cone, an irregular polygonal cone, etc.
  • the depth of the microneedle cavity 1111 is 0.001 ⁇ m-1000 ⁇ m, and the maximum diameter is 0.005-3000 ⁇ m.
  • the distance between the microneedle cavities 1111 is 4 ⁇ m-1000 ⁇ m.
  • the molding liquid when filling the molding liquid, can be introduced into the molding cavity 11 by means of pressurized spraying, atomized spraying, roller coating, brushing, injection, screen printing, or scraper extrusion. .
  • the molding liquid when filling the molding liquid, the molding liquid is introduced into the molding die 1 , and the molding liquid is extruded and filled into the plurality of molding cavities 11 through a scraper.
  • the top surface of the molding die 1 is flat, and the molding liquid can be introduced into each molding cavity 11 by scraper extrusion, while basically ensuring that the liquid level of the molding liquid in the molding cavity 11 is equal to that of the molding cavity 11
  • the top surface is flat, which is beneficial to ensuring the consistency of the amount of molding liquid in each molding cavity 11.
  • filling the molding liquid can be divided into single filling or multiple filling.
  • a single injection of the molding liquid is used to fill the molding cavity 11 and the microneedle cavity 1111 with the molding liquid, thereby obtaining a structure in which the microneedle 3 and the base 4 are made of an integrated material.
  • the molding liquid is filled into the microneedle cavity 1111 and the molding cavity 11 by introducing the molding liquid twice.
  • the molding liquid is first introduced into the microneedle cavity 1111.
  • the molding liquid can be filled into the microneedle cavity 1111 through a sponge or a sponge.
  • Other structures remove the molding liquid in the molding cavity 11, and the molding liquid in the microneedle cavity 1111 is solidified and molded to obtain the microneedle 3; then the molding liquid is introduced into the molding cavity 11, and solidified and molded to obtain the substrate 4.
  • This method can be used Different molding liquids mold the microneedles 3 and the base 4, and are suitable for the preparation of microneedle patches with different materials for the microneedles 3 and the base 4.
  • the microneedles 3 and the substrate 4 with a more layered structure can also be prepared by introducing the molding liquid three or more times.
  • the molding liquid includes a solution capable of solidifying a molded skeleton material, including but not limited to acrylonitrile-butadiene-styrene copolymer (ABS), ethylene-vinyl acetate copolymer , polyvinylidene chloride, polyfluoroene, polyperfluoroene, polyacrylonitrile, polyvinyl ketone, dextran, cellulose, heparin, hyaluronic acid (hyaluronic acid), alginate, etc.
  • ABS acrylonitrile-butadiene-styrene copolymer
  • ethylene-vinyl acetate copolymer polyvinylidene chloride
  • polyfluoroene polyperfluoroene
  • polyacrylonitrile polyvinyl ketone
  • dextran cellulose
  • cellulose heparin
  • hyaluronic acid hyaluronic acid
  • the forming liquid also includes active ingredients for medicinal or cosmetic purposes, and the active ingredients may be trace amounts of active substances, DNA, RNA, pharmaceutical preparations and vaccines.
  • the gas in the microneedle cavity 1111 needs to be eliminated before the molding liquid is solidified and formed.
  • the way to eliminate the gas in the microneedle cavity 1111 can be: after introducing the molding liquid into the molding mold 1, centrifugal the molding mold 1 to generate centrifugal force in the molding liquid and introduce it into the microneedle cavity 1111 to discharge the gas; or it can be : Apply vacuum before introducing the molding liquid to the mold 1. This removes most of the air before filling the forming mold 1 .
  • the air may be heated after introducing the molding liquid into the mold 1 . This removes the air from the microneedle cavity 1111 by causing the air to expand and rise through the deposition solution and out of the forming mold 1 .
  • the bubbles in the microneedle cavity 1111 can be led out by applying ultrasonic waves.
  • the molding surface 111 is an air-permeable and liquid-impermeable structure, and a vacuum is evacuated at the bottom of the molding surface 111 to discharge the gas in the microneedle cavity 1111 and introduce the molding liquid into the microneedle cavity 1111 . in the microneedle cavity 1111.
  • a pressure gradient can be formed between the upper surface and the lower surface of the molding surface 111 , thereby promoting the gas in the microneedle cavity 1111 to pass through the molding surface 111 and be discharged from the microneedle cavity 1111 .
  • the molding surface 111 may have an air-permeable and liquid-impermeable structure, while other parts of the molding mold 1 may have an air-permeable and liquid-impermeable structure, or the entire molding mold 1 may have an air-permeable and liquid-impermeable structure. It is a breathable and liquid-impermeable structure.
  • the molding mold 1 is placed in a vacuum suction device, and then the bottom of the molding mold 1 is sucked under a negative pressure environment of 8000-10000 Pa, so that the molding liquid is completely Fill the microneedle cavity 1111 in the mold 1 .
  • the bottom of the mold 1 can be provided with a hole that is connected to the vacuum suction device, and the hole diameter is set to 20-1000nm, so that the vacuum suction device can suck the molding liquid downward through the hole, but will not allow the molding liquid to pass through. hole into the vacuum suction device.
  • the humidity in the vacuum suction device can be set between 25% and 40%. time, preferably, the humidity in this embodiment is set to 32%-35%.
  • the solidification and molding method of the molding liquid can adopt heating curing, thermal convection drying, thermal conduction drying and/or thermal radiation drying, normal temperature convection drying, normal temperature static drying, low temperature convection drying, low temperature static drying, One or more combinations of reduced pressure drying, normal pressure drying, microwave drying, chemical cross-linking, and UV curing.
  • the solidification and molding method of the molding liquid is to air-dry at a temperature of 20-25°C for 3-4 hours to avoid decomposition of the active ingredients in the molding liquid.
  • the wind speed is controlled within the range of 6-9m/s, so that the molding liquid will not be blown out of the mold 1, and the solidification rate will not be reduced due to too low wind speed, affecting production efficiency.
  • the substrate film 5 needs to be affixed to the base 4 formed on the mold 1.
  • the present invention improves the laminating method. Further improvements are made, which are described below through specific examples.
  • "aligning and attaching the substrate film 5 with an adhesive surface to the forming mold 1" includes the following operations:
  • the control unit receives the position information of the forming mold 1 and at the same time transmits the operation information to the positioning unit 76.
  • the positioning unit 76 adjusts the forming mold 1 to the preset position of the first area 711;
  • the substrate film 6 with the substrate film 5 is placed in the second area 712, the position information of the substrate film 6 in the second area 712 is identified through the second positioning unit 72, and the The position information of the substrate diaphragm 6 is transmitted to the control unit;
  • the control unit receives the position information of the substrate diaphragm 6 and at the same time transmits the operation information to the alignment unit 76.
  • the alignment unit 76 adjusts the substrate diaphragm to the preset position of the second area 712;
  • the alignment unit 76 transfers the forming mold 1 and the substrate film 6 to the laminating area 713 for alignment and overlap;
  • the pressing unit 77 presses the forming mold 1 and the substrate film 6 so that the substrate film 5 and the base 4 are bonded.
  • the position of the substrate diaphragm 6 in the second area 712 is adjusted so that the forming mold 1 and the substrate diaphragm 6 have a corresponding positional relationship, and then the alignment unit 76 can be used to adjust the position of the substrate diaphragm 6 .
  • the forming mold 1 is accurately pressed onto the substrate diaphragm 6 to avoid misalignment problems caused by positional deviations of the forming mold 1 .
  • one embodiment of the present invention provides an alignment and laminating device 7, which includes:
  • the operating area 71 is provided with a first area 711 for the forming mold 1 to be placed, and a second area 712 for the substrate film 6 to be placed;
  • the first positioning unit 73 is provided in the first area 711.
  • the first positioning unit 73 is used to identify the position information of the forming mold 1 in the first area 711 and transmit the position information of the forming mold 1 to the control unit;
  • the second positioning unit 72 is provided in the second area 712.
  • the second positioning unit 712 is used to identify the position information of the substrate diaphragm 6 in the second area 712, and position the substrate diaphragm 6 in the second area 712. 6 position information is transmitted to the control unit;
  • a control unit configured to receive the position information of the forming mold 1 and the position information of the substrate diaphragm 6, and at the same time transmit operation information to the alignment unit 76;
  • the positioning unit 76 is used to receive the operation information of the control unit, move the forming mold 1 to a preset position, move the substrate film 6 to a preset position, and move the forming mold 1 and the substrate film Piece 6 performs overlapping;
  • the pressing unit 77 is used to press the overlapping forming mold 1 and the substrate film 6 to bond the substrate film to the substrate.
  • the operating area 71 also includes a laminating area 713 for aligning the mold 1 and the substrate film 6 .
  • the alignment unit 76 can be in the first area 711 and the substrate film 6 . It can move freely in the second area 712 and the fitting area 713 .
  • control unit has calculation and storage functions, and can send operation information according to the graphic data provided by the first positioning unit 73 and the second positioning unit 72 to control the alignment unit. 76 actions.
  • the first positioning unit 73 and the second positioning unit 72 are selected from a visual alignment device, an ultrasonic positioning device or an infrared positioning device.
  • the first area 711 is provided with a first conveying device 74 for supplying the forming mold 1
  • the second area 712 is provided with a second conveying device 75 for supplying the substrate film 6 .
  • the alignment unit 76 includes a first manipulator 761 and a second manipulator 762.
  • the first manipulator 761 is used for moving the forming mold 1; the second manipulator 762 is used for the lining. Movement of bottom diaphragm 6.
  • the pressing unit 77 is selected from a roller device or a pressing device.
  • the pressing surface of the pressing device is a flexible panel and presses the forming mold 1 and the substrate diaphragm 6 from top to bottom. combine.
  • an alignment and laminating device 2 which includes:
  • the operating area 21 is provided with a first area 211 for placing the forming mold 1 and a second area 212 for placing the substrate film 6;
  • the positioning unit 23 is provided in the first area 211.
  • the positioning unit 23 is used to identify the position information of the forming mold 1 in the first area 211 and transmit the position information of the forming mold 1 to the control unit;
  • a control unit configured to receive the position information of the forming mold 1 and at the same time transmit operation information to the alignment unit 22;
  • the positioning unit 22 is provided in the second area 212.
  • the positioning unit 22 is used to receive the operation information of the control unit and move the position of the substrate diaphragm 6 in the second area 212 so that the The positions of the substrate diaphragm 6 and the forming mold 1 correspond to each other;
  • the overturning and pressing unit 24 is used to overturn and press the forming mold 1 located in the first area 211 onto the substrate film 6 in the second area 212 so that the substrate film 5 and the substrate 4 are bonded.
  • the alignment and bonding device 2 also includes a bracket 28, a moving guide rail 27, a first moving clamp 25 and a second moving clamp 26.
  • the bracket 28 is disposed on the operating area 21, so The moving guide rail 27 is located on the bracket 28 and is located at the top of the first area 211 and the second area 212.
  • the alignment unit 22 is connected to the first moving clamp 25.
  • the positioning unit 23 is connected to the second moving clamp 26, the first moving clamp 25 and the second moving clamp 26 are displaceably disposed on the moving guide rail 27, and can be moved through the first moving clamp 25.
  • the moving clamp 25 and the second moving clamp 26 adjust the positions of the alignment unit 22 and the positioning unit 23 accordingly, thereby improving the adaptability to the positions of the forming mold 1 and the substrate film 6 .
  • the alignment unit may be a single device or a combination of multiple devices.
  • the alignment unit 22 is selected from a robot, and the alignment unit 22 can move arbitrarily in the XYZ axis coordinate system of the first area 211 .
  • the positioning unit 23 may be a visual positioning device, an ultrasonic positioning device or an infrared positioning device.
  • the positioning unit 23 is selected from a visual alignment device.
  • control unit has calculation and storage functions, and can send operation information according to the graphic data provided by the positioning unit 23 to control the action of the alignment unit 22 .
  • the flipping and pressing unit 24 includes a laminating plate 241 and a flipping mechanism 242.
  • the laminating plate 241 is located in the first area 211.
  • the flipping mechanism 242 is connected to the laminating plate 241.
  • the laminating plate 241 is connected to the laminating plate 241.
  • the plywood 241 is provided with a plurality of vacuum nozzles for adsorbing and fixing the forming mold 1 .
  • a spring is provided between the laminating plate 241 and the flipping mechanism 242 to connect each other.
  • the gap between the forming mold 1 and the substrate diaphragm 6 can be avoided during the pressing process. Excessive pressing to avoid damage to the microneedle 3 caused by excessive pressing force.
  • the turning mechanism 242 is selected from a robot hand.
  • the second area 212 is provided with a transport mechanism 29 for supplying the substrate film 6 .
  • the transmission mechanism 29 includes a conveyor belt 291 and a motor 292.
  • the conveyor belt 291 is To transport the substrate film 6, the motor 292 is used to drive the transfer belt.
  • the visual alignment device starts to take pictures of the molding mold 1. And transmit the position information of the forming mold 1 to the control unit (not shown in the figure) for storage and reading.
  • the control unit performs calculations based on the position information and transmits the operation instructions to the adjustment unit to allow the adjustment unit to Adjust the position of the substrate diaphragm 6 on the conveyor belt 291 until the substrate diaphragm 6 and the forming mold 1 are in a relatively confirmed position.
  • the substrate diaphragm 6 In order to achieve fast and accurate fitting, the substrate diaphragm 6 The position of the forming mold 1 is adjusted to be mirror symmetrical with respect to the center line of the operating area 21 . Then, the forming mold 1 on the laminating plate 241 is turned over to the substrate film 6 through the laminating and flipping mechanism 242 for lamination, so that multiple substrates 4 are adhered to the multiple substrate films 5 one by one, and the substrate films 5 are separated. And the molding mold 1, the microneedles 3 and the substrate 4 are peeled off from the microneedle cavity 1111 and the molding cavity 11 in the molding mold 1, and combined with the substrate film 5, that is, the production of the microneedle patch is completed.

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Abstract

一种微针贴片的制备方法及成型模具(1)、对位贴合装置(7)，制备方法包括以下操作步骤：在成型模具(1)上填充成型液，成型模具(1)包括框架结构(12)和嵌入于框架结构(12)上的成型面(111)，框架结构(12)为刚性材料，成型面(111)为柔性材料，成型面(111)上设置有多个微针腔(1111)，微针腔(1111)用于微针(3)的成型，成型液导入成型面(111)及微针腔(1111)中，成型液固化成型，得到基底(4)以及连接于基底(4)上的多个微针(3)，基底(4)的一侧露出于成型模具(1)表面；将具有粘性表面的衬底膜(5)对位贴附于成型模具(1)上，使衬底膜(5)带有粘性表面压合粘贴基底(4)；衬底膜(5)携带基底(4)和微针(3)从成型模具(1)脱出，得到微针贴片。微针贴片的制备方法能够有效保证微针(3)脱模的完整性和对位的准确性。

Description

一种微针贴片的制备方法及成型模具、对位贴合装置 技术领域
本发明属于微针制备技术领域，具体涉及一种微针贴片的制备方法及成型模具、对位贴合装置。
背景技术
微针作为一种新型透皮给药技术，由多个微米级的细小针尖以阵列的方式连接在基座上组成，针体一般高10-2000微米、宽10-50微米，能定向穿过角质层，产生微米尺寸的机械通道，将药物直接置于表皮或上部真皮层，不用通过角质层即可参与微循环，发挥药理反应，并且可以基本做到无痛微创，方便安全，应用场景广泛。虽然微针产品发展前景广阔，但目前仍需解决产业化、给药量、生产工艺质量标准等问题。
目前微针从给药方式上主要分为实心微针、包衣微针、可溶性微针和空心微针。其中可溶性微针用生物可降解的聚合物材料搭载药物活性成分制成可溶解的微针在穿透皮肤角质层后，针体上含有的功能性药物成分会随着可溶性微针的溶解共同释放，使得药物分子物理性透过角质层屏障，从而实现皮下组织及人体对药物的渗透吸收。此种给药方式并不需要像其他微针那样需要在插入针体给药后移除针体，可溶解微针仅需在给药后移除敷贴即可，无创、安全、高效，患者依从性好，因此成为了市场上的主流。
可溶性微针的制备工艺主要采用的是模具注入，具体的制备过程是将相应药物及佐剂注入到模具中，待烘干固化成形后脱模，即可收集到制备的微针。模具注塑技术可通过控制模具来控制微针的特性，例如形态、尺寸、阵列密度等。该方法简单易行，并且可在一般实验室中进行，然而该方法的在扩大生产时缺点也很突出，具体存在以下几方面的问题：
1、当所述成型模具为刚性材料时，由于刚性材料难以发生形变，在脱模时，微针的尖端容易受到应力发生断裂，导致微针不具有较好的穿透性能，同时断裂的微针影响下一批次微针贴片的制备；采用硅胶作为模具，能够减小脱模时所受到的应力，故现有成型模具多采用硅胶等机械强度较低的材料制备得到， 但是硅胶在使用过程中容易产生形变，影响后续成型液注入步骤以及后续的贴合步骤的精确定位，同时在微针成型干燥的过程中，其基底会产生的一定的收缩作用，进而带动模具发生形变，影响微针成型效果，也不利于脱模。
2、通常微针制备工艺都是采用人工单个或单行将成型液注入成型模具上，再进行刮涂，这种方式效率较低，不适用于微针贴片的工业化生产。
3、在大规模生产时成型模具的定位问题，不采用人工定位的情况下无法对成型模具进行自动精确定位，导致最终成型模具与衬底膜片不能对位贴合，降低了生产效率的同时也影响最终产品质量。
发明内容
针对现有微针贴片的生产过程中存在模具变形和脱模时容易断针的问题，本发明提供了一种成型模具、对位贴合装置及微针贴片的制备方法。
本发明解决上述技术问题所采用的技术方案如下：
一方面，本发明提供了一种微针贴片的制备方法，包括以下操作步骤：
在成型模具上填充成型液，所述成型模具包括框架结构和嵌入于所述框架结构上的成型面，所述框架结构为刚性材料，所述成型面为柔性材料，所述成型面上设置有多个微针腔，所述微针腔用于微针的成型，成型液导入成型面及微针腔中，成型液固化成型，得到基底以及连接于基底上的多个微针，基底的一侧露出于所述成型模具表面；
将具有粘性表面的衬底膜对位贴附于所述成型模具上，使衬底膜带有粘性表面压合粘贴所述基底；
所述衬底膜携带所述基底和所述微针从所述成型模具脱出，得到微针贴片。
可选的，所述刚性材料选自单晶硅、不锈钢、铝板、钛板、硅酸盐玻璃、石英玻璃、陶瓷、聚四氟乙烯、聚醚醚酮或丙烷磺酸吡啶嗡盐。
可选的，所述成型面的数量为多个，多个所述成型面间隔设置于所述框架结构上。
可选的，所述框架结构上设置有多个成型孔，所述成型面位于所述成型孔的底面，所述成型孔由所述成型面封闭以形成成型腔，所述成型腔用于基底的成型。
可选的，所述成型模具还包括柔性板，所述柔性板位于所述框架结构的底 部并与所述成型面一体成型。
可选的，所述成型模具还包括涂布板，所述涂布板可分离地设置于所述框架结构上，且所述涂布板上与多个所述成型面对应的位置开设有多个通孔，所述通孔由所述成型面封闭以形成成型腔。
可选的，填充成型液时，将成型液导入至所述成型模具上，通过刮板将成型液挤压填充至多个所述成型腔中，所述成型面为透气不透液结构，在所述成型面的底部抽真空，以将所述微针腔中的气体排出，使成型液导入至所述微针腔中。
可选的，所述“将具有粘性表面的衬底膜对位贴附于所述成型模具上”包括以下操作：
将成型模具置于第一区域中，通过第一定位单元识别所述成型模具在所述第一区域的位置信息，并将所述成型模具的位置信息输送至控制单元；
控制单元接收所述成型模具的位置信息，同时向对位单元输送操作信息，对位单元将成型模具调整至第一区域的预设位置；
将带有衬底膜的衬底膜片置于第二区域中，通过第二定位单元识别所述衬底膜片在所述第二区域的位置信息，并将所述衬底膜片的位置信息输送至控制单元；
控制单元接收所述衬底膜片的位置信息，同时向对位单元输送操作信息，对位单元将衬底膜片调整至第二区域的预设位置；
对位单元将成型模具和衬底膜片转移至贴合区域进行对位重叠；
压合单元对成型模具和衬底膜片进行压合，衬底膜与基底粘合。
另一方面，本发明提供了一种成型模具，包括框架结构和嵌入于所述框架结构上的成型面，所述框架结构为刚性材料，所述成型面为柔性材料，所述成型面上设置有多个微针腔，所述微针腔用于微针的成型。
可选的，所述成型面的数量为多个，多个所述成型面间隔设置于所述框架结构上。
可选的，所述框架结构上设置有多个成型孔，所述成型面位于所述成型孔的底面，所述成型孔由所述成型面封闭以形成成型腔，所述成型腔用于基底的成型。
可选的，所述成型模具还包括柔性板，所述柔性板位于所述框架结构的底部并与所述成型面一体成型。
可选的，所述成型模具还包括涂布板，所述涂布板可分离地设置于所述框架结构上，且所述涂布板上与多个所述成型面对应的位置开设有通孔，所述通孔由所述成型面封闭以形成成型腔。
另一方面，本发明提供了一种对位贴合装置，包括：
操作区，设置有供成型模具放置的第一区域和供衬底膜片放置的第二区域；
第一定位单元，设置于所述第一区域，第一定位单元用于识别所述成型模具在所述第一区域的位置信息，并将所述成型模具的位置信息输送至控制单元；
第二定位单元，设置于所述第二区域，第二定位单元用于识别所述衬底膜片在所述第二区域的位置信息，并将所述衬底膜片的位置信息输送至控制单元；
控制单元，用于接收所述成型模具的位置信息和所述衬底膜片的位置信息，同时向对位单元输送操作信息；
对位单元，用于接收所述控制单元的操作信息，并移动所述成型模具至预设位置，移动所述衬底膜片至预设位置，并将成型模具和衬底膜片进行对位重叠；
压合单元，用于将对位重叠的成型模具和衬底膜片进行压合，使衬底膜与基底粘合。
可选的，所述操作区还包括用于成型模具和衬底膜片对位贴合的贴合区域，所述对位单元可在所述第一区域、所述第二区域和所述贴合区域中自由移动。
可选的，所述第一定位单元和所述第二定位单元选自视觉对位装置、超声波定位装置或红外线定位装置。
可选的，所述第一区域设置有用于供应成型模具的第一传送装置，所述第二区域设置有用于供应衬底膜片的第二传送装置。
可选的，所述对位单元包括第一机械手和第二机械手，所述第一机械手用于所述成型模具的移动；所述第二机械手用于所述衬底膜片的移动。
可选的，所述压合单元选自滚轮装置、贴压装置。
根据本发明提供的微针贴片的制备方法，通过将成型液填充于成型模具上， 形成基底以及连接与基底上的多个微针，采用柔性材料和刚性材料结合制备成型模具，所述成型面为柔性材料，相对于刚性材料，柔性材料具有可形变的特性，这有益地提供极其温和的脱模过程，可以减小微针脱模过程中受微针腔的挤压应力，通过将柔性材料的成型面固定于刚性材料的框架结构上，使得所述框架结构对于所述成型面具有支撑和固定作用，用于保持所述成型面形态的稳定性，可避免所述成型面在成型液固化收缩的过程中发生形变，进而有效改善微针的成型效果和脱模完整性，同时也利于提高后续衬底膜片的对位精准性。
在进行脱模时，通过外部的衬底膜粘附于所述基底上，由所述衬底膜将所述基底和微针从成型模具中带出，有利于保证微针脱出方向的一致性，进而避免微针由于受力不均匀导致的折断问题。
附图说明
图1是本发明提供的成型模具的结构示意图；
图2是本发明提供的成型模具的另一实施结构示意图；
图3是本发明提供的成型模具的另一实施结构示意图；
图4是本发明提供的成型模具的截面示意图；
图5是本发明一实施例提供的对位贴合装置的结构示意图；
图6是本发明另一实施例提供的对位贴合装置的结构示意图；
图7是本发明另一实施例提供的对位贴合装置的另一视角结构示意图；
图8是本发明提供的微针贴片的结构示意图。
说明书附图中的附图标记如下：
1、成型模具；11、成型腔；111、成型面；1111、微针腔；112、成型孔；113、通孔；12、框架结构；13、涂布板；14、柔性板；2、对位贴合装置；21、操作区；211、第一区域；212、第二区域；22、对位单元；23、定位单元；24、翻转压合单元；241、贴合板；242、翻转机构；25、第一移动夹；26、第二移动夹；27、移动导轨；28、支架；29、传送机构；291、传送带；292、电机；3、微针；4、基底；5、衬底膜；6、衬底膜片；7、对位贴合装置；71、操作区；711、第一区域；712、第二区域；713、贴合区域；72、第二定位单元；73、第一定位单元；74、第一传送装置；75、第二传送装置；76、对位单元；761、第一机械手；762、第二机械手；77、压合单元。
具体实施方式
为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明提供了一种微针贴片的制备方法，包括以下操作步骤：
在成型模具1上填充成型液，所述成型模具1包括框架结构12和嵌入于所述框架结构12上的成型面111，所述框架结构12为刚性材料，所述成型面111为柔性材料，所述成型面111上设置有多个微针腔1111，所述微针腔1111用于微针3的成型，成型液导入成型面111及微针腔1111中，成型液固化成型，得到基底4以及连接于基底4上的多个微针3，基底4的一侧露出于所述成型模具1表面；
将具有粘性表面的衬底膜5对位贴附于所述成型模具1上，使衬底膜5带有粘性表面压合粘贴所述基底4；
所述衬底膜5携带所述基底4和所述微针3从所述成型模具1脱出，得到微针贴片，所述微针贴片的结构如图8所示。
将成型液填充于成型模具1上，形成基底4以及连接于基底4上的多个微针3，采用柔性材料和刚性材料结合制备成型模具1，所述成型面111为柔性材料，相对于刚性材料，柔性材料具有可形变的特性，这有益地提供极其温和的脱模过程，可以减小微针3脱模过程中受微针腔1111的挤压应力，通过将柔性材料的成型面111固定于刚性材料的框架结构12上，使得所述框架结构12对于所述成型面111具有支撑和固定作用，用于保持所述成型面111形态的稳定性，可避免所述成型面111在成型液固化收缩的过程中发生形变，进而有效改善微针3的成型效果和脱模完整性，同时也利于提高后续衬底膜片5的对位精准性。
同时，在进行脱模时，通过外部的衬底膜5粘附于所述基底4上，由所述衬底膜5将所述基底4和微针3从成型模具1中带出，有利于保证微针3脱出方向的一致性，进而避免微针3由于受力不均匀导致的折断问题。
在一些实施例中，所述刚性材料包括不限于单晶硅、不锈钢、铝板、钛板、硅酸盐玻璃、石英玻璃、陶瓷、聚四氟乙烯、聚醚醚酮(PEEK)、丙烷磺酸吡啶嗡盐等，所述铝板可经过电镀或阳极氧化处理形成，所述柔性材料选自硅氧烷。
如图1和图3所示，在一实施例中，所述成型面111的数量为多个，多个 所述成型面111间隔设置于所述框架结构12上。
通过在同一成型模具1上设置多个成型面111，可在进行成型液填充时，一次性进行多个微针贴片的填充和固化成型操作，有利于提高生产效率。
在不同的实施例中，所述成型模具1可通过不同的结构实现，具体的：
如图1所示，在一实施例中，所述框架结构12上设置有多个成型孔112，所述成型面111位于所述成型孔112的底面，所述成型孔112由所述成型面111封闭以形成成型腔11，所述成型腔11用于基底4的成型。
如图2所示，在一实施例中，所述成型模具1还包括柔性板14，所述柔性板14位于所述框架结构12的底部并与所述成型面111一体成型。
如图3所示，在另一实施例中，所述成型模具1还包括涂布板13，所述涂布板13可分离地设置于所述框架结构12上，且所述涂布板13上与多个所述成型面111对应的位置开设有多个通孔113，所述通孔113由所述成型面111封闭以形成成型腔11，所述成型腔11用于基底4的成型。
本实施例通过涂布板13精准的将微针成型液注入于成型模具1相应的位置，而不是现有技术中直接在成型模具1上标注的位置进行注入，本实施例提供的方式减少了因成型模具使用过程中形变对注入位置的精确性产生的影响。并且，通过涂布板批量对成型液进行注入，提高了涂布效率。
由于所述微针腔1111中容易留存有气泡，因此，在填充成型液的初期，需要预留多余的成型液以备后续排出气泡后微针腔1111的成型液的补充，所述成型腔11作为承接成型液的腔体，具有保留部分成型液的作用，在后续去除气泡操作中，所述成型腔11中的成型液进入所述微针腔1111中进行补充，同时所述成型腔11也限制基底4的成型形状。
在一些实施例中，所述成型腔11的水平截面为长方形、椭圆形等任何形状。
在一实施例中，所述成型腔11的深度为0.01cm-0.2cm。
所述成型腔11的深度与所述基底4的厚度相关，可通过所需的基底4厚度对应设置所述成型腔11的深度，具体的，由于本制备方法中采用衬底膜5以粘附所述基底4，因此，在后续使用过程中主要由所述衬底膜5提供必要的机械强度，可相应减小所述基底4的厚度，以减低材料成本。
在一些实施例中，多个所述成型腔11呈矩阵排布或无规则分散排布。
在优选的实施例中，多个所述成型腔11呈矩阵排布，相邻的两个所述成型腔11等距间隔，以利于后续进行衬底膜5压合粘贴时的对位操作。
在一些实施例中，所述微针腔1111为尖端朝向所述成型面111内部的尖锥形腔体，如圆尖锥、椭圆形尖锥、规则多边形尖锥、不规则多边形尖锥等。
在一些实施例中，所述微针腔1111的深度为0.001μm-1000μm，最大直径为0.005-3000μm。同时，为了保证微针阵列具有一定密度，所述微针腔1111之间的距离为4μm-1000μm。
在不同实施例中，填充成型液时，可采用加压喷射、雾化喷射、辊涂、刷涂、注射、丝网印刷、刮板挤压的方式将成型液导入到所述成型腔11中。
在一实施例中，填充成型液时，将成型液导入至所述成型模具1上，通过刮板将成型液挤压填充至多个所述成型腔11中。所述成型模具1的顶面为平面，通过刮板挤压的方式可以将成型液导入至各个成型腔11中，同时基本保证成型腔11中的成型液的液面高度与所述成型腔11的顶面持平，有利于保证各个成型腔11中成型液量的一致性。
在不同的实施例中，填充成型液可分为单次填充或多次填充。
例如：在一实施例中，采用单次导入成型液的方式将成型液填充于所述成型腔11和所述微针腔1111中，得到微针3和基底4为一体材料的结构。
在另一实施例中，采用两次导入成型液的方式将成型液分别填充至微针腔1111中和成型腔11中，先将成型液导入至微针腔1111中，此时可通过海绵或其他结构去除所述成型腔11中的成型液，微针腔1111中的成型液固化成型得到微针3；然后再往成型腔11中导入成型液，固化成型得到基底4，该种方式可采用不同的成型液成型微针3和基底4，适用于微针3和基底4材料不同的微针贴片的制备。
在其他实施例中，还可采用三次或三次以上导入成型液的方式制备得到更多层结构的微针3和基底4。
在一些实施例中，所述成型液包括能够固化成型的骨架材料的溶液，所述骨架材料包括且不限于丙烯腈-丁二烯-苯乙烯共聚物(ABS)、乙烯-乙酸乙烯酯共聚物、聚偏二氯乙烯、聚氟代烯、聚全氟烯、聚丙烯腈、聚乙烯基酮、右旋糖苷、纤维素、肝素、透明质酸(玻尿酸)、藻酸酯等。
在一些实施例中，所述成型液还包括用于起到药用或美容用途的活性成分，所述活性成分可以为微量活性物质、DNA、RNA、药物制剂和疫苗。
在一些实施例中，为避免微针腔1111中残留的气泡影响微针3的成型，在成型液固化成型之前，需要对微针腔1111中的气体进行排除。
排除微针腔1111中的气体的方式可以是：将成型液导入成型模具1后，通过对成型模具1离心的方式使成型液产生离心力而导入至微针腔1111中，排出气体；也可以是：在将成型液导入至成型模具1上之前施加真空。这样就在填充成型模具1之前移除大部分空气。也可以是：在将成型液导入成型模具1上之后加热空气。这样就通过使空气膨胀并上升通过沉积溶液并离开成型模具1而移除微针腔1111的空气。也可以是：通过施加超声波的方式，使微针腔1111中的气泡导出。
在一优选的实施例中，所述成型面111为透气不透液结构，在所述成型面111的底部抽真空，以将所述微针腔1111中的气体排出，使成型液导入至所述微针腔1111中。
在真空抽吸条件下，能在成型面111的上表面和下表面之间形成压力梯度，进而促进微针腔1111中的气体穿过所述成型面111而排出所述微针腔1111。
具体的，在不同的实施例中，可以是所述成型面111为透气不透液结构，而所述成型模具1的其他部分为不透气不透液结构，也可以是所述成型模具1整体为透气不透液结构。
在本实施例中，将成型液导入成型模具1后，将成型模具1放入真空抽吸装置中，然后在8000-10000Pa的负压环境下对成型模具1底部进行抽吸，使得成型液完全填充于成型模具1中的微针腔1111内。成型模具1底部可以设置有与真空抽吸装置相对接的孔，孔径的大小设置为20-1000nm，使得真空抽吸装置可以通过孔对成型液向下进行抽吸，但不会让成型液从孔中流入真空抽吸装置中。为了快速使成型液干燥固化，同时避免过度干燥影响成型液流动性(流动性较差无法实现微针腔1111中的完全填充)，真空抽吸装置中的湿度可以设置在25％-40％之间，优选的，本实施例的湿度设置为32％-35％。
在一些实施例中，所述成型液的固化成型方式可采用加热固化、热对流干燥、热传导干燥和/或热辐射干燥、常温对流干燥、常温静置干燥、低温对流干燥、低温静置干燥、减压干燥、常压干燥、微波干燥、化学交联、UV固化中的一种或多种组合。
在一实施例中，所述成型液的固化成型方式为在20-25℃的温度下风干3-4h，以避免成型液中活性成分的分解。同时，将风速控制在范围6-9m/s内，这样既不会将成型液吹出成型模具1，也不会因风速太低导致固化速率降低，影响生产效率。
在本制备方法的贴合步骤中，需要将衬底膜5粘贴至所述成型模具1上成型的基底4上，存在贴合位置偏差的问题，为解决该问题，本发明对贴合方法进行了进一步的改进，以下通过具体实施例进行说明。
在一些实施例中，所述“将具有粘性表面的衬底膜5对位贴附于所述成型模具1上”包括以下操作：
将成型模具1置于第一区域711中，通过第一定位单元73识别所述成型模具1在所述第一区域711的位置信息，并将所述成型模具1的位置信息输送至控制单元；
控制单元接收所述成型模具1的位置信息，同时向对位单元76输送操作信息，对位单元76将成型模具1调整至第一区域711的预设位置；
将带有衬底膜5的衬底膜片6置于第二区域712中，通过第二定位单元72识别所述衬底膜片6在所述第二区域712的位置信息，并将所述衬底膜片6的位置信息输送至控制单元；
控制单元接收所述衬底膜片6的位置信息，同时向对位单元76输送操作信息，对位单元76将衬底膜片调整至第二区域712的预设位置；
对位单元76将成型模具1和衬底膜片6转移至贴合区域713进行对位重叠；
压合单元77对成型模具1和衬底膜片6进行压合，衬底膜5与基底4粘合。
通过识别所述成型模具1在所述第一区域711的位置信息，识别所述衬底膜片在所述第二区域712的位置信息，调整所述成型模具1在第一区域711的位置，调整所述衬底膜片6在所述第二区域712的位置，使得所述成型模具1和所述衬底膜片6具有对应的位置关系，进而通过所述对位单元76能够将所述成型模具1精准地压合至所述衬底膜片6上，避免所述成型模具1的位置偏差导致的对位不准的问题。
如图5所示，本发明的一实施例提供了一种对位贴合装置7，包括：
操作区71，设置有供成型模具1放置的第一区域711、供衬底膜片6放置的第二区域712；
第一定位单元73，设置于所述第一区域711，第一定位单元73用于识别所述成型模具1在所述第一区域711的位置信息，并将所述成型模具1的位置信息输送至控制单元；
第二定位单元72，设置于所述第二区域712，第二定位单元712用于识别所述衬底膜片6在所述第二区域712的位置信息，并将所述衬底膜片 6的位置信息输送至控制单元；
控制单元，用于接收所述成型模具1的位置信息和所述衬底膜片6的位置信息，同时向对位单元76输送操作信息；
对位单元76，用于接收所述控制单元的操作信息，并移动所述成型模具1至预设位置，移动所述衬底膜片6至预设位置，并将成型模具1和衬底膜片6进行对位重叠；
压合单元77，用于将对位重叠的成型模具1和衬底膜片6进行压合，使衬底膜与基底粘合。
在本实施例中，所述操作区71还包括用于成型模具1和衬底膜片6对位贴合的贴合区域713，所述对位单元76可在所述第一区域711、所述第二区域712和所述贴合区域713中自由移动。
在本实施例中，所述控制单元具备计算和储存功能，并能根据所述第一定位单元73和所述第二定位单元72所提供的图形数据发出操作信息，以控制所述对位单元76的动作。
在本实施例中，所述第一定位单元73和所述第二定位单元72选自视觉对位装置、超声波定位装置或红外线定位装置。
在本实施例中，所述第一区域711设置有用于供应成型模具1的第一传送装置74，所述第二区域712设置有用于供应衬底膜片6的第二传送装置75。
在本实施例中，所述对位单元76包括第一机械手761和第二机械手762，所述第一机械手761用于所述成型模具1的移动；所述第二机械手762用于所述衬底膜片6的移动。
在本实施例中，所述压合单元77选自滚轮装置或贴压装置，所述贴压装置的贴压面为柔性面板，从上至下对成型模具1和衬底膜片6进行压合。
如图6和图7所示，本发明的另一实施例提供了一种对位贴合装置2，包括：
操作区21，设置有供所述成型模具1放置的第一区域211和放置有衬底膜片6的第二区域212；
定位单元23，设置于所述第一区域211，定位单元23用于识别所述成型模具1在所述第一区域211的位置信息，并将所述成型模具1的位置信息输送至控制单元；
控制单元，用于接收所述成型模具1的位置信息，同时向对位单元22输送操作信息；
对位单元22，设置于所述第二区域212，对位单元22用于接收所述控制单元的操作信息，并移动所述衬底膜片6在所述第二区域212的位置以使所述衬底膜片6和所述成型模具1的位置相对应；
翻转压合单元24，用于将位于所述第一区域211的成型模具1翻转压合至所述第二区域212的衬底膜片6上，使衬底膜5与基底4粘合。
在本实施例中，所述对位贴合装置2还包括有支架28、移动导轨27、第一移动夹25和第二移动夹26，所述支架28设置于所述操作区21上，所述移动导轨27位于所述支架28上，且所述移动导轨27位于所述第一区域211和所述第二区域212的顶部，所述对位单元22连接于所述第一移动夹25上，所述定位单元23连接于所述第二移动夹26上，所述第一移动夹25和所述第二移动夹26可位移地设置于所述移动导轨27上，可通过所述第一移动夹25和所述第二移动夹26对应调整所述对位单元22和所述定位单元23的位置，进而提高对于成型模具1和衬底膜片6位置的适配性。
在一些实施例中，所述对位单位可为单个装置或多个装置组合。
在本实施例中，所述对位单元22选自机械手，所述对位单元22可在所述第一区域211的XYZ轴坐标系中任意移动。
在一些实施例中，所述定位单元23可以为视觉对位装置、超声波定位装置或红外线定位装置。
在本实施例中，所述定位单元23选自视觉对位装置。
在本实施例中，所述控制单元具备计算和储存功能，并能根据所述定位单元23所提供的图形数据发出操作信息，以控制所述对位单元22的动作。
在本实施例中，所述翻转压合单元24包括贴合板241和翻转机构242，所述贴合板241位于所述第一区域211，所述翻转机构242连接所述贴合板241，所述贴合板241上设置有多个用于吸附固定所述成型模具1的真空吸嘴。
在本实施例中，所述贴合板241与所述翻转机构242之间设置有弹簧以相互连接，通过所述弹簧能够在压合的过程中，避免成型模具1与衬底膜片6之间过度压合，避免过大的压合力导致微针3损伤的问题。
在本实施例中，所述翻转机构242选自机械手。
在本实施例中，所述第二区域212设置有用于供应衬底膜片6的传送机构29。
具体的，所述传送机构29包括传送带291和电机292，所述传送带291用 于输送所述衬底膜片6，所述电机292用于驱动所述转送带的运行。
在本实施例中，固化成型后的成型模具1运送至贴合板241上表面后，通过贴合板241上的真空吸嘴对其位置进行固定，随后视觉对位装置开始对成型模具1进行拍照，并将成型模具1的位置信息传输至控制单元(图中未示出)中进行储存并读取，控制单元根据该位置信息进行运算，并将操作指令传输至调整对位单位，让对位单位对传送带291上的衬底膜片6的位置进行调整，直至衬底膜片6与成型模具1处于相对确认的位置，在本实施例中，为了实现快速精准的贴合，衬底膜片6与成型模具1的位置被调整为相对于操作区21的中心线镜像对称。再通过贴合翻转机构242将贴合板241上的成型模具1翻转至衬底膜片6处进行压合，使多个基底4一一对应粘贴至多个衬底膜5上，分离衬底膜5和成型模具1，微针3和基底4从成型模具1中的微针腔1111和成型腔11内剥离，并与衬底膜5结合，即完成微针贴片的生产。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (19)

  1. 一种微针贴片的制备方法，其特征在于，包括以下操作步骤：
    在成型模具上填充成型液，所述成型模具包括框架结构和嵌入于所述框架结构上的成型面，所述框架结构为刚性材料，所述成型面为柔性材料，所述成型面上设置有多个微针腔，所述微针腔用于微针的成型，成型液导入成型面及微针腔中，成型液固化成型，得到基底以及连接于基底上的多个微针，基底的一侧露出于所述成型模具表面；
    将具有粘性表面的衬底膜对位贴附于所述成型模具上，使衬底膜带有粘性表面压合粘贴所述基底；
    所述衬底膜携带所述基底和所述微针从所述成型模具脱出，得到微针贴片。
  2. 根据权利要求1所述的微针贴片的制备方法，其特征在于，所述刚性材料包括单晶硅、不锈钢、铝板、钛板、硅酸盐玻璃、石英玻璃、陶瓷、聚四氟乙烯、聚醚醚酮或丙烷磺酸吡啶嗡盐。
  3. 根据权利要求1所述的微针贴片的制备方法，其特征在于，所述成型面的数量为多个，多个所述成型面间隔设置于所述框架结构上。
  4. 根据权利要求3所述的微针贴片的制备方法，其特征在于，所述框架结构上设置有多个成型孔，所述成型面位于所述成型孔的底面，所述成型孔由所述成型面封闭以形成成型腔，所述成型腔用于基底的成型。
  5. 根据权利要求4所述的微针贴片的制备方法，其特征在于，所述成型模具还包括柔性板，所述柔性板位于所述框架结构的底部并与所述成型面一体成型。
  6. 根据权利要求3所述的微针贴片的制备方法，其特征在于，所述成型模具还包括涂布板，所述涂布板可分离地设置于所述框架结构上，且所述涂布板上与多个所述成型面对应的位置开设有通孔，所述通孔由所述成型面封闭以形成成型腔。
  7. 根据权利要求4～6任意一项所述的微针贴片的制备方法，其特征在于，填充成型液时，将成型液导入至所述成型模具上，通过刮板将成型液挤压填充至多个所述成型腔中，所述成型面为透气不透液结构，在所述成型面的底部抽真空，以将所述微针腔中的气体排出，使成型液导入至所述微针腔中。
  8. 根据权利要求1所述的微针贴片的制备方法，其特征在于，所述“将具有粘性表面的衬底膜对位贴附于所述成型模具上”包括以下操作：
    将成型模具置于第一区域中，通过第一定位单元识别所述成型模具在所述第一区域的位置信息，并将所述成型模具的位置信息输送至控制单元；
    控制单元接收所述成型模具的位置信息，同时向对位单元输送操作信息，对位单元将成型模具调整至第一区域的预设位置；
    将带有衬底膜的衬底膜片置于第二区域中，通过第二定位单元识别所述衬底膜片在所述第二区域的位置信息，并将所述衬底膜片的位置信息输送至控制单元；
    控制单元接收所述衬底膜片的位置信息，同时向对位单元输送操作信息，对位单元将衬底膜片调整至第二区域的预设位置；
    对位单元将成型模具和衬底膜片转移至贴合区域进行对位重叠；
    压合单元对成型模具和衬底膜片进行压合，衬底膜与基底粘合。
  9. 一种成型模具，其特征在于，包括框架结构和嵌入于所述框架结构上的成型面，所述框架结构为刚性材料，所述成型面为柔性材料，所述成型面上设置有多个微针腔，所述微针腔用于微针的成型。
  10. 根据权利要求9所述的成型模具，其特征在于，所述成型面的数量为多个，多个所述成型面间隔设置于所述框架结构上。
  11. 根据权利要求9所述的成型模具，其特征在于，所述框架结构上设置有多个成型孔，所述成型面位于所述成型孔的底面，所述成型孔由所述成型面封闭以形成成型腔，所述成型腔用于基底的成型。
  12. 根据权利要求9所述的成型模具，其特征在于，所述成型模具还包括柔性板，所述柔性板位于所述框架结构的底部并与所述成型面一体成型。
  13. 根据权利要求9所述的成型模具，其特征在于，所述成型模具还包括涂布板，所述涂布板可分离地设置于所述框架结构上，且所述涂布板上与多个所述成型面对应的位置开设有通孔，所述通孔由所述成型面封闭以形成成型腔。
  14. 一种对位贴合装置，其特征在于，包括：
    操作区，设置有供成型模具放置的第一区域和供衬底膜片放置的第二区域；
    第一定位单元，设置于所述第一区域，第一定位单元用于识别所述成型模具在所述第一区域的位置信息，并将所述成型模具的位置信息输送至控制单元；
    第二定位单元，设置于所述第二区域，第二定位单元用于识别所述衬底膜片在所述第二区域的位置信息，并将所述衬底膜片的位置信息输送至控制单元；
    控制单元，用于接收所述成型模具的位置信息和所述衬底膜片的位置信息，同时向对位单元输送操作信息；
    对位单元，用于接收所述控制单元的操作信息，并移动所述成型模具至预设位置，移动所述衬底膜片至预设位置，并将成型模具和衬底膜片进行对位重叠；
    压合单元，用于将对位重叠的成型模具和衬底膜片进行压合，使衬底膜与基底粘合。
  15. 根据权利要求14所述的对位贴合装置，其特征在于，所述操作区还包括用于成型模具和衬底膜片对位贴合的贴合区域，所述对位单元可在所述第一区域、所述第二区域和所述贴合区域中自由移动。
  16. 根据权利要求14所述的对位贴合装置，其特征在于，所述第一定位单元和所述第二定位单元选自视觉对位装置、超声波定位装置或红外线定位装置。
  17. 根据权利要求14所述的对位贴合装置，其特征在于，所述第一区域设置有用于供应成型模具的第一传送装置，所述第二区域设置有用于供应衬底 膜片的第二传送装置。
  18. 根据权利要求14所述的对位贴合装置，其特征在于，所述对位单元包括第一机械手和第二机械手，所述第一机械手用于所述成型模具的移动和调整；所述第二机械手用于所述衬底膜片的移动和调整。
  19. 根据权利要求14所述的对位贴合装置，其特征在于，所述压合单元选自滚轮装置、贴压装置。
PCT/CN2023/095919 2022-05-25 2023-05-24 一种微针贴片的制备方法及成型模具、对位贴合装置 WO2023227003A1 (zh)

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