WO2023246262A1 - 一种微针药膜片的制备方法 - Google Patents

一种微针药膜片的制备方法 Download PDF

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Publication number
WO2023246262A1
WO2023246262A1 PCT/CN2023/089149 CN2023089149W WO2023246262A1 WO 2023246262 A1 WO2023246262 A1 WO 2023246262A1 CN 2023089149 W CN2023089149 W CN 2023089149W WO 2023246262 A1 WO2023246262 A1 WO 2023246262A1
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WIPO (PCT)
Prior art keywords
microneedle
drug
drug film
film forming
molding
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PCT/CN2023/089149
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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 WO2023246262A1 publication Critical patent/WO2023246262A1/zh

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • 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
    • A61M2037/0046—Solid microneedles
    • 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 specifically relates to a method for preparing microneedle drug diaphragms.
  • Dissolvable microneedles can be divided into integrated microneedles and split microneedles according to different production processes.
  • Integrated microneedles are solidified and formed directly on the mold using a film forming liquid, while split microneedles need to be coated with API or The needle tip liquid of the active material is coated with the base liquid and then solidified.
  • Two different microneedle preparation processes involve a coating process.
  • a coating mold is usually used to inject the microneedle liquid into the microneedle molding mold for solidification and molding.
  • GMP Article 189 stipulates that at every stage of production, products and materials should be protected from microbial and other contamination.
  • the traditional production method of microneedle drug film is to first use a drug film mesh to shape the polymer solution to form the shape of the drug film.
  • the polymer solution in the plate tank (the drug film mesh plate often has a certain height, so the polymer solution is easy to remain in the tank during scraping) will cause contamination due to contact with the subsequently injected polymer solution.
  • the drug film mold After the drug film mold has been used several times, They all need to be cleaned and disinfected separately, which greatly reduces production efficiency. Due to the fine structure and small size of the film mold, it is very inconvenient to clean. In automated production, there is material contamination caused by incomplete cleaning.
  • the existing method of reusing the medical film screen usually involves placing an excessive amount of medical film liquid on the medical film screen. During long-term placement, the water in the medical film liquid evaporates and dries out, affecting the scraping effect.
  • the drug film After the drug film is formed, it needs to be dried and solidified. In actual production, if it dries too fast, it will easily lead to white spots, cracks, agglomeration, and edge warping of the drug film, which will affect the final product quality.
  • the medicine film also has certain requirements on the way the wind flows during the air-drying step. Disordered wind direction will cause uneven drying of the medicine film, resulting in white spots or cracks, and will also reduce drying efficiency. Moreover, due to the requirements of GMP regulations for a sterile production environment, production plants generally use isolators to isolate the production lines in a sterile environment. The cost of isolators is expensive, and ordinary drug film drying equipment is large in size, further limiting the availability of the production line. space.
  • the present invention provides a method for preparing microneedle drug films.
  • the invention provides a method for preparing microneedle drug diaphragms, which includes the following operations:
  • a plurality of microneedle molding areas are provided on the molding mold, and a plurality of microneedle cavities are provided on the surface of the microneedle molding area.
  • the multiple microneedle cavities are filled with a microneedle molding liquid and solidified to obtain a needle body;
  • a disposable mesh plate is detachably placed on the forming mold.
  • the disposable mesh plate is provided with a plurality of through holes corresponding to the positions of the microneedle molding areas. The surface of the microneedle molding area is closed. The through hole is used to form a drug film forming cavity, the drug film forming liquid is packaged in a sealed container, the drug film forming liquid required for a single coating is applied on the disposable screen through the sealed container, and the drug film is applied to the disposable screen plate by a scraper.
  • the molding liquid is scraped and applied into multiple film molding cavities;
  • the viscosity of the drug film forming liquid is 1,000 cps to 200,000 cps.
  • the volume of the drug film forming liquid applied in the closed container in a single time is the sum of the volumes of multiple drug film forming cavities.
  • the drug film forming liquid is extruded from a closed container in a strip shape on the top side of the disposable mesh plate, and the drug film forming liquid is scraped from the top side of the disposable mesh plate to the disposable mesh plate using a scraper. On the other side of the top, fill the film forming liquid into the film forming cavity.
  • the disposable mesh plate is made of plastic mesh plate or metal mesh plate.
  • the molding mold includes a support plate and a plurality of microneedle molding areas, the shape of the microneedle molding area is consistent with the shape of the drug film to be prepared, and the plurality of microneedle molding areas are embedded in the mold at intervals.
  • the support plate is made of rigid material
  • the microneedle molding area is made of flexible breathable material.
  • vacuum the molding mold with a vacuum degree of ⁇ 0.1Mpa and a vacuuming time of 0.5 to 10 minutes.
  • multiple molding molds are arranged side by side at intervals from top to bottom, and unidirectional laminar flow wind is formed between the plurality of molding molds to dry the medicine film forming liquid on the molding molds.
  • the temperature of the unidirectional laminar flow wind is 15-45 degrees Celsius.
  • the temperature is 20-25 degrees Celsius, and the wind speed is 0.5-2.5m/s.
  • a laminar flow drying device for drying processing.
  • the laminar flow drying device includes a box, Filter, air inlet fan, exhaust fan and material rack, the material rack is located in the box, the air inlet fan and the exhaust fan are respectively located at the front and rear sides of the material rack, the filter screen is located in the At the air inlet of the air inlet, the material rack includes a plurality of material trays, a plurality of the material trays are arranged side by side at intervals from top to bottom, and a plurality of the forming molds are placed on the plurality of material trays one by one. , sealing pads are provided between the left and right sides of two adjacent material pallets for sealing.
  • a disposable mesh plate is used to replace the existing reused drug film mesh plate.
  • the disposable mesh plate is recycled and discarded after a single scraping coating, and no need Cleaning the disposable stencil can effectively improve production efficiency, and at the same time avoid the risk of contamination caused by the film forming fluid remaining on the disposable stencil to subsequent production;
  • the medical film forming liquid can be Encapsulated in a sealed container, it can effectively prevent the solvent of the film forming liquid from evaporating and ensure the quality of the film forming liquid.
  • Figure 1 is a schematic structural diagram of the forming mold and disposable screen plate provided by the present invention
  • Figure 2 is a schematic cross-sectional view of the forming mold and the disposable screen plate provided by the present invention
  • Figure 3 is a schematic structural diagram of the laminar flow drying device provided by the present invention.
  • Figure 4 is a side view of the laminar flow drying device provided by the present invention.
  • FIG. 5 is an enlarged schematic view of position A in FIG. 4 .
  • the present invention provides a method for preparing microneedle drug diaphragms, which includes the following operations:
  • a plurality of microneedle molding areas 11 are provided on the molding mold 1.
  • a plurality of microneedle cavities 111 are provided on the surface of the microneedle molding area 11.
  • the multiple microneedle cavities 111 are filled with a microneedle molding liquid and solidified to obtain a needle body. ;
  • the disposable mesh plate 2 is detachably placed on the forming mold 1.
  • the disposable mesh plate 2 is provided with a plurality of through holes 21 at positions corresponding to the plurality of microneedle molding areas 11.
  • the microneedle molding The surface of the area 11 closes the through hole 21 to form the drug film forming cavity 3.
  • the drug film forming liquid is sealed in a closed container, and the drug film required for a single coating is applied on the disposable screen through the closed container. Forming liquid, apply the film forming liquid to multiple film forming cavities 3 through a scraper;
  • the disposable screen plate 2 and the molding mold 1 are separated and recycled, the drug film forming liquid on the molding mold 1 is dried, solidified and formed to obtain a drug film; the microneedle drug film is obtained by demoulding.
  • the disposable mesh plate 2 is used to replace the existing reusable drug film mold.
  • the disposable mesh plate 2 is recycled after a single scraping. No need Cleaning the disposable screen plate 2 can effectively improve production efficiency, and at the same time avoid the risk of contamination caused by the film forming liquid remaining on the disposable screen plate 2 to subsequent production; on the other hand, during the scraping operation
  • the film can be The molding liquid is sealed in a sealed container, which can effectively prevent the solvent of the film forming liquid from evaporating and ensure the quality of the film forming liquid.
  • the viscosity of the drug film forming liquid is 1,000 cps to 200,000 cps.
  • the viscosity of the drug film forming liquid By limiting the viscosity of the drug film forming liquid to between 1,000 cps and 200,000 cps, it is conducive to the scraping operation of the drug film forming liquid with a scraper, and avoids the inconsistency of the drug film forming liquid on the forming mold 1 or the disposable screen plate 2 Wetting shrinkage problem, improve the scraping effect; if the viscosity of the drug film forming liquid is too low, the fluidity of the drug film forming liquid on the surface of the forming mold 1 or the disposable screen plate 2 is too strong, resulting in spreading everywhere and making it difficult to satisfy the scraping effect. coating conditions.
  • the volume of the drug film forming liquid applied in the closed container in a single time is the sum of the volumes of multiple drug film forming cavities 3 .
  • the drug film forming liquid is extruded from a closed container in a strip shape on the top side of the disposable mesh plate 2, and the drug film forming liquid is scraped from the top side of the disposable mesh plate 2 to disposable net On the other side of the top of the plate 2, the drug film forming liquid is filled into the drug film forming cavity 3.
  • the drug film forming liquid can also be introduced into the drug film forming cavity 3 by spin coating or other scraping methods.
  • the disposable mesh 2 is made of plastic mesh, metal plate, wood board or other materials that comply with relevant GMP regulations.
  • the disposable mesh board 2 is a PET mesh plate or a PVC mesh plate.
  • the amount of drug film forming liquid applied each time in the present invention is just enough to fill a plurality of the drug film forming cavities 3 or slightly more than the plurality of drug film forming cavities.
  • the amount of 3 therefore, if the drug film forming liquid cannot produce a good infiltration effect with the disposable screen plate 2, it will easily cause it to shrink without infiltration, which will lead to the drug film forming liquid on different positions on the disposable screen plate 2
  • the problem of uneven distribution eventually leads to insufficient filling of the drug film forming liquid in some drug film forming cavities 3, and the excess drug film forming liquid on the disposable screen plate 2 will contaminate the drug film forming liquid in the next operation.
  • the PET material used in this embodiment has a good infiltration effect with the skeleton material and solvent of the drug film forming liquid, which can effectively avoid the problem of non-wetting shrinkage of the drug film forming liquid on the disposable screen 2, which is beneficial to the scraper.
  • the scraping operation of the drug film forming liquid ensures that the drug film forming liquid is introduced into multiple drug film forming cavities 3 .
  • other materials, such as metal mesh such as metal mesh, the problem of non-wetting and shrinkage of the drug film forming liquid on the disposable mesh 2 may easily occur.
  • the microneedle molding area 11 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 demoulding, 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 11 is made of 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 111 during the microneedle demoulding process.
  • the forming mold 1 includes a support plate 12 and a plurality of microneedle molding areas 11.
  • the shape of the microneedle molding area 11 is consistent with the shape of the drug film to be prepared.
  • the plurality of microneedle molding areas 11 are The areas 11 are embedded in the support plate 12 at intervals, and the support plate 12 is made of rigid material, and the microneedle molding area 11 is made of flexible breathable material.
  • the rigid material is selected from the group consisting of monocrystalline silicon, stainless steel, aluminum plates, titanium plates, silicate glass, quartz glass, ceramics, polytetrafluoroethylene, polyetheretherketone (PEEK), pyridine propane sulfonate Hum salt, etc.
  • the flexible material is selected from silicone.
  • a flexible material and a rigid material are combined to prepare the molding mold 1.
  • the microneedle molding area 11 of the flexible material is fixed on the support plate 12 of the rigid material, so that the support plate 12 has a structure for the microneedle molding area 11.
  • the supporting and fixing functions are used to maintain the stability of the shape of the microneedle molding area 11; the microneedle cavity 111 provided on the microneedle molding area 11 is used for solidification and molding of microneedles, and the use of flexible materials is beneficial to reducing microneedle microneedle formation.
  • the stress experienced during the needle demoulding process improves the integrity of the microneedle after demoulding.
  • the microneedle molding area 11 is fixed in shape through the support plate 12 of rigid material, which can prevent the microneedle molding area 11 from being The microneedle molding liquid deforms during the solidification and shrinkage process, thereby effectively improving the molding effect and demoulding integrity of the microneedle.
  • the microneedle cavity 111 is a pointed cone-shaped cavity with the tip facing the inside of the microneedle forming area 11, such as a conical cone, an elliptical cone, a regular polygonal cone, and an irregular polygonal cone. wait.
  • the depth of the microneedle cavity 111 is 0.001 ⁇ m-1000 ⁇ m, and the maximum diameter is 0.005-3000 ⁇ m.
  • the distance between the microneedle cavities 111 is 4 ⁇ m-1000 ⁇ m.
  • the molding mold 1 after separating the disposable screen plate 2 and before drying the molding mold 1, the molding mold 1 is vacuumed, the vacuum degree is ⁇ 0.1Mpa, and the vacuuming time is 0.5 to 10 minutes.
  • multiple molding molds 1 when performing the drying operation, are spaced side by side from top to bottom, and unidirectional laminar flow is formed between the multiple molding molds 1 to carry out the drying process on the film forming liquid on the molding molds 1 dry.
  • the temperature of the unidirectional laminar flow wind is 15-45°C, especially 20-25°C for better drying effect, and the wind speed is 0.5-2.5m/s.
  • the drying rate can be slightly increased and the production capacity can be increased while ensuring the drying quality.
  • a laminar flow drying device 4 for drying.
  • the laminar flow drying device 4 includes a box 41, a filter, an air inlet fan 42, an exhaust fan 43 and materials.
  • Rack 44, the material rack 44 is located in the box 41, the air inlet fan 42 and the exhaust fan 43 are located at the front and rear sides of the material rack 44, and the filter screen is located at the side of the air inlet fan 42.
  • the material rack 44 includes a plurality of material trays 441.
  • the plurality of material trays 441 are arranged side by side at intervals from top to bottom.
  • a plurality of the forming molds 1 are placed on the plurality of material trays 441 in one-to-one correspondence.
  • Two adjacent ones Sealing pads 442 are provided between the left and right sides of each material pallet 441 for sealing, so that the wind formed by the air inlet fan 42 and the exhaust fan 43 can only flow in the front and rear directions between the two material pallets 441 .
  • Directional flow thus forming a stable laminar flow and achieving better drying effect.
  • the sealing gasket 442 uses a silicone gasket.

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Abstract

本发明提供了一种微针药膜片的制备方法，包括以下操作：将一次性网板可分离地置于成型模具上，一次性网板对应多个微针成型区的位置开设有多个通孔，微针成型区的表面封闭通孔以形成药膜成型腔，将药膜成型液封装于密闭容器中，通过密闭容器在一次性网板上施加单次涂布所需的药膜成型液，通过刮刀将药膜成型液刮涂至多个药膜成型腔中；将一次性网板与成型模具分离移除，对成型模具上的药膜成型液进行干燥处理，固化成型得到药膜；脱模得到微针药膜片。本发明提供的微针药膜片的制备方法可以有效提高生产效率，同时解决污染风险的问题。

Description

一种微针药膜片的制备方法 技术领域
本发明属于微针制备技术领域，具体涉及一种微针药膜片的制备方法。
背景技术
可溶解微针根据生产工艺的不同可以分为一体式微针和分体式微针，一体式微针是采用药膜成型液直接在模具上固化成型，而分体式微针则需要先涂布含有API或活性物质的针尖液，再涂布基底液后固化成型。两种不同的微针制备工艺都涉及到涂布工艺，在涂布过程中通常需要采用涂布模具将微针液注入至微针成型模具中进行固化成型。然而，药品生产质量管理规范GMP第一百八十九条规定，在生产的每一阶段，应当保护产品和物料免受微生物和其他污染。因此，为了达到GMP规范对生产过程中的卫生标准，传统的微针药膜生产方式是先通过使用药膜网板对高分子溶液进行定型以形成药膜的形状，为了避免残留在药膜网板槽内(药膜网板往往具有一定高度，因此在刮涂时槽内容易残留高分子溶液)的高分子溶液与后续注入的高分子溶液接触而造成污染，药膜模具使用过若干次后都需要进行单独的清洗、消毒，大幅度降低了生产效率，由于药膜模具结构精细、尺寸小，清洗起来十分不便，在自动化生产中存在因清洗不尽而产生的物料污染的情况。
另外，现有重复使用药膜网板的方式通常是将过量的药膜液置于药膜网板上，药膜液在长期放置过程中出现水分蒸发变干的情况，影响刮涂效果。
药膜成型后需要进行干燥固化，在实际生产中，如果干燥过快，容易导致药膜出现白斑、破裂、结块以及边缘翘起的情况，影响最终的产品品质。
药膜在风干步骤中对风的流动方式也有一定要求，紊乱的风向会使得药膜干燥不均匀，从而出现白斑或裂痕，同时还会降低干燥效率。并且，由于GMP规范对无菌生产环境的要求，生产厂房一般采用隔离器将生产线隔离在无菌的环境当中，隔离器的成本昂贵，普通药膜干燥设备体积较大，进一步限制了生产线的可用空间。
发明内容
针对现有大批量生产过程中微针药膜的制备存在生产效率低和物料污染的问题，本发明提供了一种微针药膜片的制备方法。
本发明解决上述技术问题所采用的技术方案如下：
本发明提供了一种微针药膜片的制备方法，包括以下操作：
在成型模具上设置有多个微针成型区，所述微针成型区表面设置有多个微针腔，在多个微针腔中填充微针成型液，固化得到针体；
将一次性网板可分离地置于所述成型模具上，所述一次性网板对应多个所述微针成型区的位置开设有多个通孔，所述微针成型区的表面封闭所述通孔以形成药膜成型腔，将药膜成型液封装于密闭容器中，通过所述密闭容器在一次性网板上施加单次涂布所需的药膜成型液，通过刮刀将药膜成型液刮涂至多个药膜成型腔中；
将一次性网板与成型模具分离移除，对成型模具上的药膜成型液进行干燥处理，固化成型得到药膜；脱模得到微针药膜片。
可选的，所述药膜成型液的粘度为1000cps～200000cps。
可选的，所述密闭容器单次施加的药膜成型液的体积为多个所述药膜成型腔的体积之和。
可选的，将药膜成型液由密闭容器在一次性网板的顶部一侧呈条状挤出，通过刮刀将药膜成型液由一次性网板的顶部一侧刮涂至一次性网板的顶部另一侧，将药膜成型液填充至药膜成型腔中。
可选的，所述一次性网板采用塑胶网板或金属网板。
可选的，所述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药膜形状一致，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，分离一次性网板后，对成型模具进行干燥处理之前，对成型模具进行抽真空处理，真空度≤0.1Mpa，真空抽吸时间为0.5～10min。
可选的，进行干燥处理操作时，将多个成型模具由上至下间隔并排设置，在多个成型模具之间形成单向层流风对成型模具上的药膜成型液进行干燥。
可选的，所述单向层流风的温度为15-45摄氏度，优选的，温度为20-25摄氏度，风速为0.5-2.5m/s。
可选的，设置有层流干燥装置进行干燥处理，所述层流干燥装置包括箱体、 滤网、进风机、排风机和物料架，所述物料架位于所述箱体中，所述进风机和所述排风机分别位于所述物料架的前后两侧，所述滤网位于所述进风机的进风口处，所述物料架包括多个物料托盘，多个所述物料托盘由上至下间隔并排设置，多个所述成型模具一一对应地放置于多个所述物料托盘上，相邻两个所述物料托盘的左右两侧边之间均设置有密封垫进行封闭。
根据本发明提供的微针药膜片的制备方法，采用一次性网板替代现有重复使用的药膜网板，一次性网板在进行单次的刮涂后即进行回收废弃处理，不需要对一次性网板进行清洗，从而可以有效提高生产效率，同时也避免了一次性网板上残留的药膜成型液对后续生产导致的污染风险问题；另一方面，在进行刮涂操作时，仅由密闭容器施加单次刮涂所需的药膜成型液，能够有效避免药膜成型液的浪费，同时也使得不同批的药膜成型液分离，降低污染风险，同时，将药膜成型液封装于密闭容器中，可以有效避免药膜成型液的溶剂挥发，保证药膜成型液的质量。
附图说明
图1是本发明提供的成型模具和一次性网板的结构示意图；
图2是本发明提供的成型模具和一次性网板的截面示意图；
图3是本发明提供的层流干燥装置的结构示意图；
图4是本发明提供的层流干燥装置的侧视图；
图5是图4中A处的放大示意图。
说明书附图中的附图标记如下：
1、成型模具；11、微针成型区；111、微针腔；12、支撑板；2、一次性网
板；21、通孔；3、药膜成型腔；4、层流干燥装置；41、箱体；42、进风机；43、排风机；44、物料架；441、物料托盘；442、密封垫。
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。
参见图1和图2所示，本发明提供了一种微针药膜片的制备方法，包括以下操作：
在成型模具1上设置有多个微针成型区11，所述微针成型区11表面设置有多个微针腔111，在多个微针腔111中填充微针成型液，固化得到针体；
将一次性网板2可分离地置于所述成型模具1上，所述一次性网板2对应多个所述微针成型区11的位置开设有多个通孔21，所述微针成型区11的表面封闭所述通孔21以形成药膜成型腔3，将药膜成型液封装于密闭容器中，通过所述密闭容器在一次性网板上施加单次涂布所需的药膜成型液，通过刮刀将药膜成型液刮涂至多个药膜成型腔3中；
将一次性网板2与成型模具1分离回收，对成型模具1上的药膜成型液进行干燥处理，固化成型得到药膜；脱模得到微针药膜片。
根据本发明提供的微针药膜片的制备方法，采用一次性网板2替代现有重复使用的药膜模具，一次性网板2在进行单次的刮涂后即进行回收处理，不需要对一次性网板2进行清洗，从而可以有效提高生产效率，同时也避免了一次性网板2上残留的药膜成型液对后续生产导致的污染风险问题；另一方面，在进行刮涂操作时，仅由密闭容器施加单次刮涂所需的药膜成型液，能够有效避免药膜成型液的浪费，同时也使得不同批的药膜成型液分离，降低污染风险，同时，将药膜成型液封装于密闭容器中，可以有效避免药膜成型液的溶剂挥发，保证药膜成型液的质量。
在一些实施例中，所述药膜成型液的粘度为1000cps～200000cps。
通过将所述药膜成型液的粘度限制在1000cps～200000cps之间，有利于通过刮刀对药膜成型液进行刮涂操作，避免药膜成型液在成型模具1或一次性网板2上的不浸润收缩问题，提高刮涂效果；若所述药膜成型液的粘度过低，则药膜成型液在成型模具1或一次性网板2表面的流动性过强，导致四处扩散而难以满足刮涂条件。
在一些实施例中，所述密闭容器单次施加的药膜成型液的体积为多个所述药膜成型腔3的体积之和。
通过将单次施加的药膜成型液的体积设置为多个所述药膜成型腔3的体积之和，可以有效保证单次使用的药膜成型液对于多个药膜成型腔3的完全填充，同时也避免了对于药膜成型液的浪费，在分离所述一次性网板2时，避免过多药膜液的浪费。
在一些实施例中，将药膜成型液由密闭容器在一次性网板2的顶部一侧呈条状挤出，通过刮刀将药膜成型液由一次性网板2的顶部一侧刮涂至一次性网 板2的顶部另一侧，将药膜成型液填充至药膜成型腔3中。
在其他实施例中，所述药膜成型液也可采用旋涂的方式，或是其他刮涂的方式将药膜成型液导入至所述药膜成型腔3中。
在一些实施例中，所述一次性网板2采用塑胶网板或金属板或木板等符合GMP相关法规的材料。
在优选的实施例中，所述一次性网板2采用PET网板或PVC网板。
为了避免药膜成型液的污染以及浪费，本发明中每次施加的药膜成型液为刚好能够填充多个所述药膜成型腔3的量或是稍多于多个所述药膜成型腔3的量，因此，若所述药膜成型液无法与一次性网板2产生较好的浸润效果的话，易导致其不浸润收缩，进而导致一次性网板2上不同位置上药膜成型液分布量的不均匀问题，最终导致部分药膜成型腔3中药膜成型液的填充不足，而一次性网板2上多出的药膜成型液会对下次操作的药膜成型液产生污染。本实施例中采用PET材料具有与药膜成型液的骨架材料和溶剂具有较好的浸润效果，能够有效避免药膜成型液在一次性网板2上的不浸润收缩问题，进而有利于刮刀对药膜成型液的刮涂操作，保证药膜成型液导入至多个药膜成型腔3中。而采用其他材料，如金属网板，容易出现药膜成型液在一次性网板2上的不浸润收缩问题。
当所述微针成型区11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11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111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11发生形变，同样不利于微针成型效果和脱模。
在一些实施例中，所述成型模具1包括支撑板12和多个微针成型区11，所述微针成型区11的形状与所需制备的药膜形状一致，多个所述微针成型区11间隔嵌入于所述支撑板12上，且所述支撑板12为刚性材料，所述微针成型区11为柔性透气材料。
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成型模具1，通过将柔性材料的微针成型区11固定于刚性材料的支撑板12上，使得所述支撑板12对于所述微针成型区11具有支撑和固定作用，用于保持所述微针成型区11形态的稳定性；所述微针成型区11上设置的微针腔111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12对微针成型区11进行形态固定，可避免所述微针成型区11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，所述微针腔111为尖端朝向所述微针成型区11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111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111之间的距离为4μm-1000μm。
在一些实施例中，分离一次性网板2后，对成型模具1进行干燥处理之前，对成型模具1进行抽真空处理，真空度≥0.1Mpa，真空抽吸时间为0.5～10min。
通过抽真空处理，有利于排除所述微针腔111和所述药膜成型腔3中的气泡，避免残留气泡对于微针强度和药膜完整性的影响。
在一些实施例中，进行干燥处理操作时，将多个成型模具1由上至下间隔并排设置，在多个成型模具1之间形成单向层流风对成型模具1上的药膜成型液进行干燥。
通过将多个成型模具1上下间隔设置进行单向层流风干燥处理，一方面，提高了空间利用率，有效缩小了干燥装置的空间占用；另一方面，也提高药膜上不同位置干燥质量的一致性，避免出现白斑或裂痕，提高干燥效率。
在一些实施例中，所述单向层流风的温度为15-45，特别为20-25摄氏度下有更好的干燥效果，风速为0.5-2.5m/s。
通过对于单向层流风的温度和风速控制，能够在保证干燥质量的前提下有小提高干燥速率，提高产能。
如图3～图5所示，在一些实施例中，设置有层流干燥装置4进行干燥处理，所述层流干燥装置4包括箱体41、滤网、进风机42、排风机43和物料架44，所述物料架44位于所述箱体41中，所述进风机42和所述排风机43分别位于所述物料架44的前后两侧，所述滤网位于所述进风机42的进风口处，所述物 料架44包括多个物料托盘441，多个所述物料托盘441由上至下间隔并排设置，多个所述成型模具1一一对应地放置于多个所述物料托盘441上，相邻两个所述物料托盘441的左右两侧边之间均设置有密封垫442进行封闭，使得由所述进风机42和所述排风机43形成的风只能在两个物料托盘441之间的前后方向流动，从而形成稳定的层流风，实现更好的干燥效果。
在一些实施例中，所述密封垫442采用硅胶垫。
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 (10)

  1. 一种微针药膜片的制备方法，其特征在于，包括以下操作：
    在成型模具上设置有多个微针成型区，所述微针成型区表面设置有多个微针腔，在多个微针腔中填充微针成型液，固化得到针体；
    将一次性网板可分离地置于所述成型模具上，所述一次性网板对应多个所述微针成型区的位置开设有多个通孔，所述微针成型区的表面封闭所述通孔以形成药膜成型腔，将药膜成型液封装于密闭容器中，通过所述密闭容器在一次性网板上施加单次涂布所需的药膜成型液，通过刮刀将药膜成型液刮涂至多个药膜成型腔中；
    将一次性网板与成型模具分离回收，对成型模具上的药膜成型液进行干燥处理，固化成型得到药膜；脱模得到微针药膜片。
  2. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，所述药膜成型液的粘度为1000cps～200000cps。
  3. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，所述密闭容器单次施加的药膜成型液的体积为多个所述药膜成型腔的体积之和。
  4. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，将药膜成型液由密闭容器在一次性网板的顶部一侧呈条状挤出，通过刮刀将药膜成型液由一次性网板的顶部一侧刮涂至一次性网板的顶部另一侧，将药膜成型液填充至药膜成型腔中。
  5. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，所述一次性网板采用塑胶网板或金属网板。
  6. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，所述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药膜形状一致，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。
  7. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，分离一次性网板后，对成型模具进行干燥处理之前，对成型模具进行抽真空处理，真空度≤0.1Mpa，真空抽吸时间为0.5～10min。
  8. 根据权利要求1所述的微针药膜片的制备方法，其特征在于，进行干燥处理操作时，将多个成型模具由上至下间隔并排设置，在多个成型模具之间形成单向层流风对成型模具上的药膜成型液进行干燥。
  9. 根据权利要求8所述的微针药膜片的制备方法，其特征在于，所述单向层流风的温度为15-45摄氏度，风速为0.5-2.5m/s。
  10. 根据权利要求8所述的微针药膜片的制备方法，其特征在于，设置有层流干燥装置进行干燥处理，所述层流干燥装置包括箱体、滤网、进风机、排风机和物料架，所述物料架位于所述箱体中，所述进风机和所述排风机分别位于所述物料架的前后两侧，所述滤网位于所述进风机的进风口处，所述物料架包括多个物料托盘，多个所述物料托盘由上至下间隔并排设置，多个所述成型模具一一对应地放置于多个所述物料托盘上，相邻两个所述物料托盘的左右两侧边之间均设置有密封垫进行封闭。
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JP2015100659A (ja) * 2013-11-28 2015-06-04 日本写真印刷株式会社 マイクロニードルシートの製造方法
CN107405478A (zh) * 2015-03-10 2017-11-28 富士胶片株式会社 经皮吸收片的制造方法
CN106426687A (zh) * 2016-10-17 2017-02-22 中国科学院理化技术研究所 一种用于制作聚合物微针的设备
CN216127595U (zh) * 2021-07-28 2022-03-25 上海悦肤达生物科技有限公司 制备微针的设备
CN115674522A (zh) * 2021-07-28 2023-02-03 上海悦肤达生物科技有限公司 制备微针的设备和方法

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