WO2023241213A1 - 一种分层式微针成型方法及分层式微针成型装置 - Google Patents
一种分层式微针成型方法及分层式微针成型装置 Download PDFInfo
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- WO2023241213A1 WO2023241213A1 PCT/CN2023/089167 CN2023089167W WO2023241213A1 WO 2023241213 A1 WO2023241213 A1 WO 2023241213A1 CN 2023089167 W CN2023089167 W CN 2023089167W WO 2023241213 A1 WO2023241213 A1 WO 2023241213A1
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- Prior art keywords
- molding
- microneedle
- mold
- semi
- cavity
- Prior art date
Links
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Classifications
-
- 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
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
- B29C33/0022—Multi-cavity moulds
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- 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
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
-
- 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
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/22—Component parts, details or accessories; Auxiliary operations
- B29C39/26—Moulds or cores
-
- 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
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/22—Component parts, details or accessories; Auxiliary operations
- B29C39/42—Casting under special conditions, e.g. vacuum
-
- 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
- B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
- B29C41/34—Component parts, details or accessories; Auxiliary operations
- B29C41/38—Moulds, cores or other substrates
-
- 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
-
- 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
- B29C69/00—Combinations of shaping techniques not provided for in a single one of main groups B29C39/00 - B29C67/00, e.g. associations of moulding and joining techniques; Apparatus therefore
- B29C69/02—Combinations of shaping techniques not provided for in a single one of main groups B29C39/00 - B29C67/00, e.g. associations of moulding and joining techniques; Apparatus therefore of moulding techniques only
-
- 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
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Definitions
- the invention belongs to the technical field of microneedle preparation and relates to a layered microneedle molding method and a layered microneedle molding device.
- the molding liquid is introduced into the microneedle cavity of the molding mold using atomized spraying.
- the introduction efficiency of this method is not high, and there is a waste of molding liquid and the molded microneedles contain more
- scraping is currently used to squeeze the molding fluid into the microneedle cavity on the surface of the mold.
- the existing scraping process needs to limit the viscosity of the molding fluid.
- the molding mold generally uses soft materials such as silicone resin, and silicone resin and other materials are incompatible with the molding fluid.
- the wettability is not high, which can easily lead to non-wetting shrinkage of the molding liquid on the surface of the mold. That is, the molding liquid agglomerates on the surface of the mold, resulting in no molding liquid being introduced into the top of some microneedle cavities, resulting in different amounts of molding liquid introduced into the microneedle cavities.
- the problem of inconsistency results in insufficient drug loading in microneedles and the inability to achieve good drug effects.
- Some existing molding molds such as patent CN113491675A, are provided with base molding slots on the top surface of the microneedle cavity.
- the fluidity of the microneedle molding liquid can be limited to a certain extent through this slot, vacuum suction The process will cause part of the microneedle molding liquid to enter the microneedle cavity and further reduce the microneedle molding liquid in the slot, causing the microneedle molding liquid to shrink without infiltration on the bottom surface of the slot, affecting the drug loading capacity of the microneedle cavity at different locations.
- the setting of this slot is not suitable for the scraping process, and the microneedle molding liquid will remain at the corners of the slot, thus causing a waste of active pharmaceutical ingredients. It is also inconvenient for the reuse and continuous production of the molding mold, and it is easy to be left on the edges. Corner position causes contamination.
- the size of the microneedle cavity is on the micron level, it is easy for air to remain. After scraping, vacuum conditions need to be set up for suction to introduce the molding liquid into the microneedle cavity.
- the viscosity of the molding liquid is too high, it will also affect the The efficiency of the molding liquid entering the molding cavity, and the molding liquid with high viscosity is not conducive to the extraction of bubbles from the subsequent microneedle cavity, and it is also easy to retain bubbles.
- the existing scraping process also greatly limits the viscosity requirements of the molding liquid, which can be used to prepare microneedles. Selecting the type of raw materials requires adding a large amount of excipients to the molding fluid to increase its viscosity, which in turn affects the actual drug loading capacity of the microneedle.
- the present invention provides a layered microneedle molding method and a layered microneedle molding device.
- the present invention provides a layered microneedle molding method, which includes the following steps:
- the microneedle molding mold includes a molding surface and an air extraction surface.
- a microneedle molding area for molding microneedles is provided on the microneedle molding mold.
- the microneedle molding area is made of breathable material.
- a plurality of microneedle cavities are provided on the surface of the molding surface, and a semi-closed cavity is provided to detachably cover the molding surface.
- the semi-closed cavity is filled with microneedle molding liquid, and the microneedle molding liquid is immersed in the molding surface.
- Base molding Apply the base molding liquid to the molding surface of the microneedle molding mold, solidify, mold and demould to obtain layered microneedles including microneedles and a base.
- the semi-enclosed cavity is a groove-shaped structure with a top opening, and the molding surface detachably closes the top opening of the semi-enclosed cavity.
- the molding surface of the microneedle molding mold is set downward so that the molding surface covers and closes the top opening of the semi-closed cavity, and the microneedle molding mold and the semi-enclosed cavity are The closed cavity is inverted so that the semi-closed cavity is located above the microneedle molding mold.
- the microneedle molding liquid is immersed in the molding surface.
- the air extraction surface of the microneedle molding mold is vacuumed to introduce the microneedle molding liquid into the microneedle cavity.
- the present invention provides a layered microneedle molding device, which includes a semi-closed cavity, a microneedle molding mold and a vacuum suction device.
- the semi-closed cavity is provided with a top opening, and the microneedle molding mold includes a molding device.
- the microneedle molding is provided with a microneedle molding area for molding microneedles, the microneedle molding area is made of breathable material, and the microneedle molding area extends to the molding surface and the On the air extraction surface, the microneedle molding area is provided with a plurality of microneedle cavities on the surface of the molding surface, the microneedle molding mold removably closes the top opening of the semi-closed cavity, and the molding Facing the semi-enclosed cavity, the vacuum suction device is used to perform vacuum suction on the surface of the microneedle molding mold facing away from the semi-enclosed cavity.
- Figure 1 is a schematic structural diagram of a semi-closed cavity and a microneedle molding mold provided by the present invention
- Figure 5 is an electron microscope photograph of the layered microneedles provided in Embodiment 1 of the present invention.
- Base molding The base molding liquid is applied to the molding surface 12 of the microneedle molding mold 1, solidified, molded and demoulded to obtain layered microneedles including microneedles and a base.
- the scraping operation ensures that the microneedles in different microneedle cavities 131 are With the consistency of the amount of molding liquid, even microneedle molding liquid with low viscosity can be successfully filled into the microneedle cavity 131 using this method, effectively broadening the viscosity requirements for the microneedle molding liquid, and thus broadening the requirements for the microneedle molding liquid.
- the material selection range of the microneedle molding fluid can reduce the amount of auxiliary materials used to increase the viscosity, which can effectively increase the concentration of active ingredients, which is beneficial to the development of microneedle materials and the improvement of drug loading capacity.
- the molding material of the base can be selected as a soluble material or a poorly soluble material.
- active ingredients for medicinal or cosmetic purposes can be added only to the microneedles, or active ingredients for medicinal or cosmetic purposes can be added to both the microneedles and the base.
- the active ingredients It can be trace amounts of active substances, DNA, RNA, pharmaceutical preparations and vaccines.
- the layered microneedle molding method provided by the present invention uses a low-viscosity microneedle molding liquid, it is more conducive to filling the tip of the microneedle cavity 131 and obtaining a complete microneedle structure.
- the excipients and active ingredients are in a mass ratio of (1-120): Equipped in a ratio of 1.
- the microneedle molding area 13 is made of a rigid material, since the rigid material is difficult to deform, the tip of the microneedle is susceptible to stress and breaks during demolding, resulting in the microneedle not having good penetration performance and breaking at the same time.
- Microneedles affect 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 beneficially provides extremely The gentle demoulding process can reduce the extrusion stress of the microneedle cavity 131 during the microneedle demoulding process.
- this embodiment is provided with multiple shapes and sizes and layered microneedle patches on the support plate.
- the microneedle molding area 13 has a uniform base shape, and the microneedle molding liquid in the semi-closed cavity 2 is pumped into the range of the microneedle molding area 13 through the suction effect of the vacuum suction device on the microneedle molding area 13 , avoiding additional subsequent cutting steps and waste of microneedle molding fluid.
- a plurality of the microneedle forming areas 13 are arranged in a matrix or randomly dispersed.
- the microneedle cavity 131 is a pointed cone-shaped cavity with the tip facing the inside of the microneedle forming area 13, such as a conical cone, an elliptical cone, a regular polygonal cone, and an irregular polygonal cone. wait.
- the depth of the microneedle cavity 131 is 1 ⁇ m-1000 ⁇ m, and the maximum diameter (ie, base diameter) is 5-3000 ⁇ m.
- the distance between the microneedle cavities 131 is 4 ⁇ m-1000 ⁇ m.
- the non-wetting shrinkage of the microneedle molding liquid on the surface of the microneedle molding area 13 can be effectively suppressed, ensuring that the microneedle molding liquid is The full coverage of the molding surface 12 improves the consistency of the amount of microneedle molding liquid filled in each microneedle cavity 131 .
- the microneedle molding liquid is cured and molded by air-drying at a temperature of 20-25°C for 0.5-4 hours to avoid decomposition of active ingredients in the molding liquid.
- the wind speed is controlled within the range of 0.2-6m/s, so that the molding liquid will not be blown out of the microneedle cavity 131, and the solidification rate will not be reduced due to the wind speed being too low, affecting the production efficiency.
- the microneedle molding mold 1 can be detachably The top opening of the semi-enclosed cavity 2 is closed, and the molding surface 12 faces the semi-enclosed cavity 2.
- the vacuum suction device is used to move the microneedle molding mold 1 away from the semi-enclosed cavity.
- the surface of body 2 is vacuumed.
- the layered microneedle molding device further includes a coating mold 3, which is detachably covered on the molding surface 12 of the microneedle molding mold 1.
- the coating mold 3 The mold 3 is provided with a plurality of base molding through holes 31 at positions corresponding to the plurality of microneedle molding areas 13 .
- the microneedle molding mold includes a molding surface and an air extraction surface.
- a microneedle molding area for molding microneedles is provided on the microneedle molding mold.
- the microneedle molding area is made of breathable material, and the microneedle molding The microneedle molding area extends to the molding surface and the exhaust surface.
- the microneedle molding area is provided with a plurality of microneedle cavities on the surface of the molding surface.
- a semi-closed cavity is provided to cover the molding surface.
- the semi-closed cavity The body is filled with microneedle molding liquid, and the semi-enclosed cavity is a groove-like structure with an open top.
- the molding surface of the microneedle molding mold is set downward so that the molding surface covers and seals the top of the semi-enclosed cavity. Open the opening, invert the microneedle molding mold and the semi-enclosed cavity, so that the semi-enclosed cavity is located above the microneedle molding mold, and the microneedle molding
- the viscosity of the liquid at 25°C is 1.680cps.
- the microneedle molding liquid is immersed in the molding surface.
- the minimum distance between the liquid level of the microneedle molding liquid and the molding surface is 3mm.
- the air extraction surface of the microneedle molding mold is vacuumed. Suction to introduce the microneedle molding liquid into the microneedle cavity;
- microneedle molding mold Separate the microneedle molding mold and the semi-closed cavity, remove the microneedle molding liquid outside the microneedle cavity, and air-dry and solidify the microneedle molding liquid in the microneedle cavity;
- the obtained layered microneedle was observed under an electron microscope, and the obtained electron microscope photo is shown in Figure 5. It can be seen that the layered microneedle obtained through the layered microneedle molding method provided by the present invention has a high drug loading capacity and excellent Needle shape.
- the microneedle molding mold includes a molding surface and an air extraction surface.
- a microneedle molding area for molding microneedles is provided on the microneedle molding mold.
- the microneedle molding area is made of breathable material, and the microneedle molding The microneedle molding area extends to the molding surface and the exhaust surface.
- the microneedle molding area is provided with a plurality of microneedle cavities on the surface of the molding surface.
- the molding surface is covered with a metal mesh, and the microneedle molding liquid is The metal mesh is applied to the molding surface.
- the viscosity of the microneedle molding liquid at 25°C is 1.680cps.
- a scraper is used to scrape the metal mesh, and the microneedle molding liquid is squeezed into the microneedle cavity.
- the air extraction surface of the needle molding mold performs vacuum suction to introduce the microneedle molding liquid into the microneedle cavity;
- a coating mold is used to cover the molding surface of the microneedle molding mold.
- the coating mold has multiple base molding through holes corresponding to the positions of multiple microneedle molding areas, and the base molding liquid is applied On the surface of the coating mold, scrape the base molding liquid into and fill a plurality of the base molding through holes with a scraper, perform a solidification operation on the base molding liquid, separate the coating mold and the microneedle molding mold, and demould to obtain the following composition: Microneedling and base layered microneedling.
- the obtained layered microneedles were observed under an electron microscope.
- the obtained electron micrographs are shown in Figure 6. It can be seen that the layered microneedle obtained through conventional scraping operation has a lower drug loading capacity, and at the same time, different microneedles have obvious drug loading capacity. Uneven.
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Abstract
为克服现有微针成型的刮涂工艺存在对于粘度要求高，影响微针成型和原料选择的问题，本发明提供了一种分层式微针成型方法，包括以下操作步骤：设置半封闭腔体覆盖于成型面，半封闭腔体中填充有微针成型液，微针成型液浸没所述成型面，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；分离微针成型模具和半封闭腔体，除去微针腔外部的微针成型液。同时，本发明还公开了一种分层式微针成型装置。本发明提供的分层式微针成型方法能够有效克服微针成型液在微针成型区表面的不浸润收缩问题，扩大微针成型液的粘度适用范围。
Description
本发明属于微针制备技术领域，涉及一种分层式微针成型方法及分层式微针成型装置。
在传统分层式微针制备过程中，采用雾化喷射的方式将成型液导入至成型模具的微针腔中，该种方式的导入效率不高，存在成型液浪费和成型微针中含有较多气泡的问题，为解决该问题，现有采用刮涂的方式挤压成型液使其导入成型模具表面的微针腔中，然而，现有的刮涂工艺需要限制成型液的粘度，当成型液的粘度过低时，成型液在成型模具表面的流动性过强，导致四处扩散而难以满足刮涂条件，且由于成型模具一般采用硅树脂等软质材料，而硅树脂等材料与成型液的浸润性不高，容易导致成型液在成型模具表面的不浸润收缩，即成型液在成型模具表面发生团聚，导致部分的微针腔顶部没有成型液导入，出现不同微针腔中成型液导入量不一致的问题，导致微针载药量不够，无法发挥良好的药物效果。现有一些成型模具，如专利CN113491675A所示，在微针腔的顶面设置有基底成型的槽位，通过该槽位虽然可以一定程度上限制微针成型液的流动性，但是，真空抽吸过程会导致部分微针成型液进入微针腔而进一步减少槽位中的微针成型液，导致微针成型液在槽位底面的不浸润收缩，影响不同位置微针腔的载药量，另外，该槽位的设置不适合刮膜工艺，会在槽位的边角位置残留微针成型液，从而造成药物活性成分的浪费，也不便于成型模具的重复使用和连续性生产，容易在边角位置造成污染。
另一方面，由于微针腔尺寸呈微米级别，容易留有空气，在刮涂后需要设置真空条件进行抽吸以将成型液导入微针腔中，成型液的粘度过高时，也会影响成型液进入成型腔中的效率，且粘度高的成型液不利于后续微针腔的气泡导出，同样容易残留气泡，同时，现有刮涂工艺对于成型液粘度要求也大大限制了微针制备可选原料的种类，需要在成型液中添加大量的辅料以提高其粘度，进而影响微针的实际载药量。
发明内容
针对现有微针成型的刮涂工艺存在对于粘度要求高，影响微针成型和原料选择的问题，本发明提供了一种分层式微针成型方法及分层式微针成型装置。
本发明解决上述技术问题所采用的技术方案如下：
一方面，本发明提供了一种分层式微针成型方法，包括以下操作步骤：
微针成型：微针成型模具包括成型面和抽气面，在微针成型模具上设置有用于成型微针的微针成型区，所述微针成型区为透气材料，所述微针成型区位于所述成型面的表面设置有多个微针腔，设置半封闭腔体可分离地覆盖于所述成型面，半封闭腔体中填充有微针成型液，所述微针成型液浸没所述成型面，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；分离微针成型模具和半封闭腔体，除去微针腔外部的微针成型液；
基底成型：将基底成型液施加于微针成型模具的成型面，固化成型并脱模得到包括微针和基底的分层式微针。
可选的，所述微针成型液在25℃下的粘度为1.680～50000cps。
可选的，所述半封闭腔体为顶部开口的槽状结构，所述成型面可拆卸地封闭所述半封闭腔体的顶部开口。
可选的，所述微针成型液的液面与所述成型面的最小距离大于0.1mm。
可选的，所述“微针成型”操作中，将微针成型模具的成型面向下设置，使所述成型面覆盖并封闭所述半封闭腔体的顶部开口，将微针成型模具和半封闭腔体倒置，使半封闭腔体位于微针成型模具的上方，微针成型液浸没成型面，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；
保持真空抽吸，再次倒置微针成型模具和半封闭腔体，分离微针成型模具和半封闭腔体，对成型面进行刮膜操作，将微针腔外部的微针成型液刮落至半封闭腔体中。
可选的，所述半封闭腔体的顶部开口内缘设置有密封圈，由所述微针成型模具的成型面抵接所述密封圈以封闭所述半封闭腔体。
可选的，所述半封闭腔体的顶部开口内缘设置有用于定位所述微针成型模具的阶梯槽，所述密封圈位于所述阶梯槽中。
可选的，所述微针成型模具包括支撑板和多个微针成型区，所述微针成型区的形状与所需制备的分层式微针的基底形状一致，多个所述微针成型区间隔
嵌入于所述支撑板上，且所述支撑板为刚性材料，所述微针成型区为柔性透气材料。
可选的，所述成型面的表面气压大于所述抽气面的表面气压。
可选的，所述“微针成型”操作中还包括，对微针腔中的微针成型液进行固化操作。
可选的，所述“基底成型”操作中，采用涂布模具覆盖于所述微针成型模具的成型面上，所述涂布模具对应多个所述微针成型区的位置开设有多个基底成型通孔，将基底成型液施加于所述涂布模具的表面，通过刮刀将基底成型液刮入并填充多个所述基底成型通孔，对基底成型液进行固化操作，分离涂布模具和微针成型模具，脱模得到包括微针和基底的分层式微针。
另一方面，本发明提供了一种分层式微针成型装置，包括半封闭腔体、微针成型模具和真空抽吸装置，所述半封闭腔体开设有顶部开口，微针成型模具包括成型面和抽气面，所述微针成型上设置有用于成型微针的微针成型区，所述微针成型区为透气材料，且所述微针成型区延伸至所述成型面和所述抽气面，所述微针成型区位于所述成型面的表面设置有多个微针腔，所述微针成型模具可拆卸地封闭所述半封闭腔体的顶部开口位置，且所述成型面朝向所述半封闭腔体，所述真空抽吸装置用于对所述微针成型模具背离所述半封闭腔体的表面进行真空抽吸。
根据本发明提供的分层式微针成型方法，通过采用半封闭腔体进行微针成型液的容置，同时将半封闭腔体设置于微针成型模具的成型面上，使微针成型液浸没微针成型模具的成型面，该种操作方式能够有效保证微针成型液对于微针腔的覆盖，避免微针成型液由于其自身的流动性导致出现各个微针腔导入量不一致的问题，同时，控制所述微针成型液的液面与所述成型面之间的距离，以克服微针成型液在微针成型区表面的不浸润收缩问题，配合真空抽吸操作，能够将微针成型液导入至微针腔中，将微针成型液导入至微针腔后再脱离所述半封闭腔体，对微针腔外部的微针成型液进行刮除操作，此时由于微针成型液已导入至微针腔中，刮除操作保证了不同微针腔中微针成型液量的一致性，即使是粘度较低的微针成型液也能采用该方法成功填充至微针腔中，有效扩宽了对于微针成型液的粘度要求，进而也扩宽了对于微针成型液的材料选择范围，减少增粘用的辅料量，可有效调高活性成分的浓度，利于微针材料的开发和载药量的提升。
图1是本发明提供的半封闭腔体和微针成型模具的结构示意图；
图2是本发明提供的半封闭腔体和微针成型模具的另一视角结构示意图；
图3是本发明提供的微针成型模具的截面示意图；
图4是本发明提供的涂布模具和微针成型模具的结构示意图；
图5是本发明实施例1提供的分层式微针的电镜照片；
图6是本发明对比例1提供的分层式微针的电镜照片。
说明书附图中的附图标记如下：
1、微针成型模具；11、抽气面；12、成型面；13、微针成型区；131、微
针腔；2、半封闭腔体；21、阶梯槽；22、密封圈；3、涂布模具；31、成型通孔。
1、微针成型模具；11、抽气面；12、成型面；13、微针成型区；131、微
针腔；2、半封闭腔体；21、阶梯槽；22、密封圈；3、涂布模具；31、成型通孔。
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。
参见图1～图4所示，本发明一实施例提供了一种分层式微针成型方法，包括以下操作步骤：
微针成型：微针成型模具1包括成型面12和抽气面11，在微针成型模具1上设置有用于成型微针的微针成型区13，所述微针成型区13为透气材料，所述微针成型区13位于所述成型面12的表面设置有多个微针腔131，设置半封闭腔体2可分离地覆盖于所述成型面12，半封闭腔体2中填充有微针成型液，微针成型液浸没所述成型面12，对微针成型模具1的抽气面11进行真空抽吸，使微针成型液导入微针腔131中；分离微针成型模具1和半封闭腔体2，除去微针腔131外部的微针成型液；
基底成型：将基底成型液施加于微针成型模具1的成型面12，固化成型并脱模得到包括微针和基底的分层式微针。
通过采用半封闭腔体2进行微针成型液的容置，同时将半封闭腔体2设置于微针成型模具1的成型面12上，使微针成型液浸没微针成型模具1的成型面12，该种操作方式能够有效保证微针成型液对于微针腔131的覆盖，避免微针
成型液由于其自身的流动性导致出现各个微针腔131导入量不一致的问题，同时，控制所述微针成型液的液面与所述成型面12之间的距离，以克服微针成型液在微针成型区13表面的不浸润收缩问题，配合真空抽吸操作，能够将微针成型液导入至微针腔131中，将微针成型液导入至微针腔131后再脱离所述半封闭腔体2，对微针腔131外部的微针成型液进行刮除操作，此时由于微针成型液已导入至微针腔131中，刮除操作保证了不同微针腔131中微针成型液量的一致性，即使是粘度较低的微针成型液也能采用该方法成功填充至微针腔131中，有效扩宽了对于微针成型液的粘度要求，进而也扩宽了对于微针成型液的材料选择范围，减少增粘用的辅料量，可有效调高活性成分的浓度，利于微针材料的开发和载药量的提升。
在本发明的描述中，术语“分层式微针”指代微针和基底采用不同材料制备得到的微针阵列结构，通常情况下，所述微针的成型材料可选择为可溶性材料，可溶性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，所述基底的成型材料可选择为可溶性材料或难溶性材料。根据不同的需要，可以仅在所述微针中加入药用或美容用途的活性成分，或是在所述微针和所述基底中均加入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。
在分层式微针的制备过程中，需要将微针和基底通过不同步骤进行。
在一些实施例中，所述微针成型液在25℃下的粘度为1.680～50000cps。
通过采用本发明提供的分层式微针成型方法，可有效地降低对于微针成型液的粘度要求，提高对于不同微针成型液的适用范围，当所述微针成型液25℃下的粘度处于上述范围中时，均适用于采用本发明提供的分层式微针成型方法进行制备。尤其是，本发明提供的分层式微针成型方法特别适用于常规微针成型工艺难以操作的低粘度微针成型液，低粘度微针成型液指的是微针成型液在25℃下的粘度为1.680～1000cps，本发明提供的分层式微针成型方法采用低粘度的微针成型液时，更有利于对于微针腔131尖端的填充，得到完整的微针结构。
在不同的实施例中，所述半封闭腔体2可设置为不同的结构，具体的，所述封闭腔体为槽状结构、筒状结构或是具有开口的不定型结构等。
在一些实施例中，所述微针成型液中，赋型剂与活性成分按照质量比
(1-120)：1的比例进行配备。
如图1和图2所示，在一实施例中，所述半封闭腔体2为顶部开口的槽状结构，所述成型面12可拆卸地封闭所述半封闭腔体2的顶部开口。
在一些实施例中，所述“微针成型”操作中，将微针成型模具1的成型面12向下设置，使所述成型面12覆盖并封闭所述半封闭腔体2的顶部开口，将微针成型模具1和半封闭腔体2倒置，使半封闭腔体2位于微针成型模具1的上方，微针成型液浸没成型面12，对微针成型模具1的抽气面11进行真空抽吸，使微针成型液导入微针腔131中；
保持真空抽吸，再次倒置微针成型模具1和半封闭腔体2，分离微针成型模具1和半封闭腔体2，对成型面12进行刮膜操作，将微针腔131外部的微针成型液刮落至半封闭腔体2中。
通过将所述成型模具1倒置后再对成型面12进行刮膜操作，利用微针成型液向下的重力能够更好的将模具表面的残留的微针成型液全部刮涂至半封闭腔体2中，从而实现微针成型液的循环利用，同时有效避免了因模具表面的残留液体在重复使用时产生污染，导致生产工艺和最终的产品无法满足GMP法规的相关要求。
通过将所述半封闭腔体2倒置，有利于使所述微针成型液在重力作用下向下流动并覆盖所述微针成型模具1的成型面12，需要说明的是，在其他实施例中，所述半封闭腔体2也可以不进行倒置，具体的，可将所述半封闭腔体2倾斜设置，以能够使微针成型液覆盖所述成型面12；或是不进行倒置或倾斜操作，直接将半封闭腔体2覆盖于所述成型面12上，并通过管道的方式往所述半封闭腔体2中注入微针成型液。
在一些实施例中，所述“微针成型”操作中，可将所述微针成型模具1和所述半封闭腔体2竖直设置，此时，保证所述微针成型液能够浸没所述成型面12即可。具体的，在进行所述“刮膜操作”时，也可将所述微针成型模具1竖直设置，将所述半封闭腔体2置于所述微针成型模具1的下方，以将多余的微针成型液刮落至所述半封闭腔体2中。
在一些实施例中，所述半封闭腔体2的顶部开口内缘设置有密封圈22，由所述微针成型模具1的成型面12抵接所述密封圈22以封闭所述半封闭腔体2。
在一些实施例中，所述半封闭腔体2的顶部开口内缘设置有用于定位所述微针成型模具1的阶梯槽21，所述密封圈22位于所述阶梯槽21中。
所述阶梯槽21用于限制所述微针成型模具1的位置，保证成型面12完全覆盖所述半封闭腔体2的顶部开口，所述密封圈22用于保证所述半封闭腔体2的顶部开口与所述成型面12的边缘之间的贴合，避免微针成型液的泄漏。
所述密封圈22可选自弹性橡胶密封圈。
当所述微针成型区13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；在优选的实施例中，所述微针成型区13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131的挤压应力，但由于柔性材料的可形变性，在微针及基底固化的过程中会产生收缩，以带动微针成型区13发生形变，同样不利于微针成型效果和脱模。
在优选的实施例中，所述微针成型模具1包括支撑板和多个微针成型区13，所述微针成型区13的形状与所需制备的分层式微针的基底形状一致，多个所述微针成型区13间隔嵌入于所述支撑板上，且所述支撑板为刚性材料，所述微针成型区13为柔性透气材料。
相比于现有技术中对整张成型模具进行抽吸，然后再通过后续裁剪得到与微针贴片对应的大小形状的方式，本实施例在支撑板上设置多个形状大小与分层式微针的基底形状一致的微针成型区13，并通过真空抽吸装置对微针成型区13的抽吸作用将半封闭腔体2中的微针成型液抽至微针成型区13的范围内，避免了增加后续裁剪步骤以及对于微针成型液的浪费。
在一些实施例中，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(PEEK)、丙烷磺酸吡啶嗡盐等，所述柔性材料选自硅氧烷。
本实施例采用柔性材料和刚性材料结合制备微针成型模具1，通过将柔性材料的微针成型区13固定于刚性材料的支撑板上，使得所述支撑板对于所述微针成型区13具有支撑和固定作用，用于保持所述微针成型区13形态的稳定性；所述微针成型区13上设置的微针腔131用于微针的固化成型，采用柔性材料有利于减小微针脱模过程中所受应力的作用，提高微针脱模后的完整性，同时，通过刚性材料的支撑板对微针成型区13进行形态固定，可避免所述微针成型区13在微针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。
在一些实施例中，多个所述微针成型区13呈矩阵排布或无规则分散排布。
在优选的实施例中，多个所述微针成型区13呈矩阵排布。
在一些实施例中，所述微针腔131为尖端朝向所述微针成型区13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131的深度为1μm-1000μm，最大直径(即底座直径)为5-3000μm。同时，为了保证微针阵列具有一定密度，所述微针腔131之间的距离为4μm-1000μm。
在一些实施例中，成型面12表面的气压大于抽气面11表面的气压，抽气面11表面气压小于或等于0.5Mpa，在优选的实施例中，抽气面11表面的气压小于0.1Mpa。
在上述的真空度条件下，有利于提高微针成型液进入到微针腔131的效率和深度。
在一些实施例中，真空抽吸的时间为0.5～10min。
在一些实施例中，所述微针成型液的液面与所述成型面的最小距离大于0.1mm。
在本发明的描述中，术语“所述微针成型液的液面与所述成型面12的最小距离”指的是：在所述微针成型液的液面上选取一个点，在所述成型面12上选取另一个点，当选取的两点之间的连线最短时，为“所述微针成型液的液面与所述成型面12的最小距离”。
在所述微针成型液的液面与所述成型面的最小距离大于0.1mm的条件下，能够有效抑制微针成型液在微针成型区13表面的不浸润收缩，保证微针成型液对于所述成型面12的全面覆盖，提高各微针腔131中填充的微针成型液量的一致性。
在具体的实施例中，所述微针成型液的液面与所述成型面的最小距离可以为0.1mm、0.5mm、0.9mm、1mm、2mm、3mm、5mm或8mm。
在一些实施例中，所述“微针成型”操作中还包括，对微针腔131中的微针成型液进行固化操作。
在一些实施例中，所述微针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，所述微针成型液的固化成型方式为在20-25℃的温度下风干0.5-4h，以避免成型液中活性成分的分解。同时，将风速控制在范围0.2-6m/s内，这样既不会将成型液吹出微针腔131，也不会因风速太低导致固化速率降低，影响生产效率。
如图4所示，在一些实施例中，所述“基底成型”操作中，采用涂布模具3覆盖于所述微针成型模具1的成型面12上，所述涂布模具3对应多个所述微针成型区13的位置开设有多个基底成型通孔31，将基底成型液施加于所述涂布模具3的表面，通过刮刀将基底成型液刮入并填充多个所述基底成型通孔31，对基底成型液进行固化操作，分离涂布模具3和微针成型模具1，脱模得到包括微针和基底的分层式微针。
本发明的另一实施例提供了一种分层式微针成型装置，包括半封闭腔体2、微针成型模具1和真空抽吸装置，所述半封闭腔体2开设有顶部开口，微针成型模具1包括成型面12和抽气面11，所述微针成型上设置有用于成型微针的微针成型区13，所述微针成型区13为透气材料，且所述微针成型区13延伸至所述成型面12和所述抽气面11，所述微针成型区13位于所述成型面12的表面设置有多个微针腔131，所述微针成型模具1可拆卸地封闭所述半封闭腔体2的顶部开口位置，且所述成型面12朝向所述半封闭腔体2，所述真空抽吸装置用于对所述微针成型模具1背离所述半封闭腔体2的表面进行真空抽吸。
在一些实施例中，所述分层式微针成型装置还包括有涂布模具3，所述涂布模具3可分离地覆盖于所述微针成型模具1的成型面12上，所述涂布模具3对应多个所述微针成型区13的位置开设有多个基底成型通孔31。
以下通过具体实施例对本发明进行进一步的说明：
实施例1
本实施例用于说明本发明提供的分层式微针成型方法，包括以下操作步骤：
微针成型：微针成型模具包括成型面和抽气面，在微针成型模具上设置有用于成型微针的微针成型区，所述微针成型区为透气材料，且所述微针成型区延伸至所述成型面和所述抽气面，所述微针成型区位于所述成型面的表面设置有多个微针腔，设置半封闭腔体覆盖于所述成型面，半封闭腔体中填充有微针成型液，所述半封闭腔体为顶部开口的槽状结构，将微针成型模具的成型面向下设置，使所述成型面覆盖并封闭所述半封闭腔体的顶部开口，将微针成型模具和半封闭腔体倒置，使半封闭腔体位于微针成型模具的上方，所述微针成型
液在25℃下的粘度为1.680cps，微针成型液浸没成型面，所述微针成型液的液面与所述成型面的最小距离为3mm，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；
分离微针成型模具和半封闭腔体，除去微针腔外部的微针成型液，对微针腔中的微针成型液进行风干固化；
基底成型：采用涂布模具覆盖于所述微针成型模具的成型面上，所述涂布模具对应多个所述微针成型区的位置开设有多个基底成型通孔，将基底成型液施加于所述涂布模具的表面，通过刮刀将基底成型液刮入并填充多个所述基底成型通孔，对基底成型液进行固化操作，分离涂布模具和微针成型模具，脱模得到包括微针和基底的分层式微针。
得到的分层式微针进行电镜观察，得到的电镜照片如图5所示，可以看出通过本发明提供的分层式微针成型方法得到的分层式微针具有较高的载药量和优良的针体形态。
对比例1
本对比例用于对比说明本发明提供的分层式微针成型方法，包括以下操作步骤：
微针成型：微针成型模具包括成型面和抽气面，在微针成型模具上设置有用于成型微针的微针成型区，所述微针成型区为透气材料，且所述微针成型区延伸至所述成型面和所述抽气面，所述微针成型区位于所述成型面的表面设置有多个微针腔，在所述成型面上覆盖金属网，将微针成型液通过金属网涂覆于成型面上，所述微针成型液在25℃下的粘度为1.680cps，采用刮刀对金属网进行刮膜操作，将微针成型液挤压进入微针腔，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；
对微针腔中的微针成型液进行风干固化；
基底成型：采用涂布模具覆盖于所述微针成型模具的成型面上，所述涂布模具对应多个所述微针成型区的位置开设有多个基底成型通孔，将基底成型液施加于所述涂布模具的表面，通过刮刀将基底成型液刮入并填充多个所述基底成型通孔，对基底成型液进行固化操作，分离涂布模具和微针成型模具，脱模得到包括微针和基底的分层式微针。
得到的分层式微针进行电镜观察，得到的电镜照片如图6所示，可以看出通过常规刮膜操作得到的分层式微针载药量较低，同时不同的微针载药量明显
不均匀。
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 (12)
- 一种分层式微针成型方法，其特征在于，包括以下操作步骤：微针成型：微针成型模具包括成型面和抽气面，在微针成型模具上设置有用于成型微针的微针成型区，所述微针成型区为透气材料，所述微针成型区位于所述成型面的表面设置有多个微针腔，设置半封闭腔体可分离地覆盖于所述成型面，半封闭腔体中填充有微针成型液，所述微针成型液浸没所述成型面，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；分离微针成型模具和半封闭腔体，除去微针腔外部的微针成型液；基底成型：将基底成型液施加于微针成型模具的成型面，固化成型并脱模得到包括微针和基底的分层式微针。
- 根据权利要求1所述的分层式微针成型方法，其特征在于，所述微针成型液在25℃下的粘度为1.680～50000cps。
- 根据权利要求1所述的分层式微针成型方法，其特征在于，所述半封闭腔体为顶部开口的槽状结构，所述成型面可拆卸地封闭所述半封闭腔体的顶部开口。
- 根据权利要求1所述的分层式微针成型方法，其特征在于，所述微针成型液的液面与所述成型面的最小距离大于0.1mm。
- 根据权利要求3所述的分层式微针成型方法，其特征在于，所述“微针成型”操作中，将微针成型模具的成型面向下设置，使所述成型面覆盖并封闭所述半封闭腔体的顶部开口，将微针成型模具和半封闭腔体倒置，使半封闭腔体位于微针成型模具的上方，微针成型液浸没成型面，对微针成型模具的抽气面进行真空抽吸，使微针成型液导入微针腔中；保持真空抽吸，再次倒置微针成型模具和半封闭腔体，分离微针成型模具和半封闭腔体，对成型面进行刮膜操作，将微针腔外部的微针成型液刮落至半封闭腔体中。
- 根据权利要求3所述的分层式微针成型方法，其特征在于，所述半封闭 腔体的顶部开口内缘设置有密封圈，由所述微针成型模具的成型面抵接所述密封圈以封闭所述半封闭腔体。
- 根据权利要求6所述的分层式微针成型方法，其特征在于，所述半封闭腔体的顶部开口内缘设置有用于定位所述微针成型模具的阶梯槽，所述密封圈位于所述阶梯槽中。
- 根据权利要求3所述的分层式微针成型方法，其特征在于，所述微针成型模具包括支撑板和多个微针成型区，所述微针成型区的形状与所需制备的分层式微针的基底形状一致，多个所述微针成型区间隔嵌入于所述支撑板上，且所述支撑板为刚性材料，所述微针成型区为柔性透气材料。
- 根据权利要求1所述的分层式微针成型方法，其特征在于，所述成型面的表面气压大于所述抽气面的表面气压。
- 根据权利要求1所述的分层式微针成型方法，其特征在于，所述“微针成型”操作中还包括，对微针腔中的微针成型液进行固化操作。
- 根据权利要求1所述的分层式微针成型方法，其特征在于，所述“基底成型”操作中，采用涂布模具覆盖于所述微针成型模具的成型面上，所述涂布模具对应多个所述微针成型区的位置开设有多个基底成型通孔，将基底成型液施加于所述涂布模具的表面，通过刮刀将基底成型液刮入并填充多个所述基底成型通孔，对基底成型液进行固化操作，分离涂布模具和微针成型模具，脱模得到包括微针和基底的分层式微针。
- 一种分层式微针成型装置，其特征在于，包括半封闭腔体、微针成型模具和真空抽吸装置，所述半封闭腔体开设有顶部开口，微针成型模具包括成型面和抽气面，所述微针成型上设置有用于成型微针的微针成型区，所述微针成型区为透气材料，且所述微针成型区延伸至所述成型面和所述抽气面，所述微针成型区位于所述成型面的表面设置有多个微针腔，所述微针成型模具可拆卸地封闭所述半封闭腔体的顶部开口位置，且所述成型面朝向所述半封闭腔体，所述真空抽吸装置用于对所述微针成型模具背离所述半封闭腔体的表面进行真 空抽吸。
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| CN105498082A (zh) * | 2015-12-24 | 2016-04-20 | 广州新济药业科技有限公司 | 微针芯片及其制备方法 |
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| WO2019058329A1 (en) * | 2017-09-22 | 2019-03-28 | Sabic Global Technologies B.V. | METHODS AND SYSTEMS FOR PRODUCING MICRO-NEEDLE NETWORKS |
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| CN102395354A (zh) * | 2009-06-03 | 2012-03-28 | 株式会社培旺精廉宅 | 采用多孔性底座的微针阵列及其制造方法 |
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