Preparation method of microneedle drug film sheet

Abstract

In order to overcome the problems of low production efficiency, material and equipment pollution in the preparation of microneedle drug film tablets in the existing mass production process, the present application provides a preparation method of microneedle drug film tablets, comprising the following operations: a disposable screen plate is detachably placed on the forming mold, a plurality of through holes are formed in the disposable screen plate corresponding to the positions of a plurality of microneedle forming areas, the surface of the microneedle forming area is closed to form a drug film forming cavity, the drug film forming liquid is sealed in a sealed container, the drug film forming liquid required for single coating is applied on the disposable screen plate through the sealed container, and the drug film forming liquid is scraped and coated into a plurality of drug film forming cavities through a scraper; the disposable screen plate is separated from the forming mold and removed, the drug film forming liquid on the forming mold is dried, and the drug film is obtained by solidification forming; and the microneedle drug film tablet is obtained by demolding. The preparation method of the microneedle drug film tablet provided by the present application can effectively improve the production efficiency and solve the problem of pollution risk.

Description

Technical Field

[0001] This invention belongs to the field of microneedle preparation technology, specifically relating to a method for preparing microneedle drug films. Background Technology

[0002] Soluble microneedles can be categorized into integral microneedles and split microneedles based on their manufacturing processes. Integral microneedles are formed by directly curing a drug-eluting solution onto a mold, while split microneedles require first coating a tip solution containing an API or active ingredient, followed by coating a base solution, and then curing. Both microneedle manufacturing processes involve coating, which typically requires using a coating mold to inject the microneedle solution into a microneedle forming mold for curing. However, Article 189 of the Good Manufacturing Practice (GMP) for pharmaceuticals stipulates that at every stage of production, products and materials must be protected from microbial and other contaminants. Therefore, in order to meet the hygiene standards of GMP regulations in the production process, the traditional microneedle drug film production method first uses a drug film stencil to shape the polymer solution into the shape of the drug film. In order to avoid the polymer solution remaining in the stencil groove (the drug film stencil often has a certain height, so polymer solution is easily left in the groove during coating) from coming into contact with the subsequently injected polymer solution and causing contamination, the drug film mold needs to be cleaned and disinfected separately after several uses, which greatly reduces production efficiency. Because the drug film mold has a delicate structure and small size, it is very inconvenient to clean. In automated production, there is a situation of material contamination due to incomplete cleaning.

[0003] In addition, the existing method of reusing the coating film plate usually involves placing an excessive amount of coating liquid on the coating film plate. During long-term storage, the coating liquid will evaporate and dry out, affecting the coating effect.

[0004] After the drug film is formed, it needs to be dried and cured. In actual production, if the drying is too fast, it is easy to cause white spots, cracks, lumps and edge lifting of the drug film, which will affect the final product quality.

[0005] The airflow pattern during the drying process of the drug film also has certain requirements. Turbulent airflow can lead to uneven drying of the drug film, resulting in white spots or cracks, and also reducing drying efficiency. Furthermore, due to the requirements of GMP standards for a sterile production environment, production plants generally use isolators to isolate the production line in a sterile environment. Isolators are expensive, and ordinary drug film drying equipment is bulky, further limiting the available space on the production line. Summary of the Invention

[0006] To address the problems of low production efficiency and material contamination in the preparation of microneedle drug films during existing mass production processes, this invention provides a method for preparing microneedle drug films.

[0007] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0008] This invention provides a method for preparing microneedle drug-eluting films, comprising the following steps:

[0009] Multiple microneedle forming areas are provided on the forming mold, and multiple microneedle cavities are provided on the surface of the microneedle forming areas. Microneedle forming liquid is filled into the multiple microneedle cavities and solidified to obtain the needle body.

[0010] A disposable stencil is detachably placed on the molding die. The disposable stencil has multiple through holes corresponding to the positions of multiple microneedle forming areas. The through holes are sealed on the surface of the microneedle forming areas to form a drug film forming cavity. The drug film forming liquid is encapsulated in a sealed container. The drug film forming liquid required for a single coating is applied to the disposable stencil through the sealed container. The drug film forming liquid is scraped onto multiple drug film forming cavities by a scraper.

[0011] The disposable mesh plate is separated from the molding mold and removed. The drug film forming liquid on the molding mold is dried and solidified to obtain a drug film. The microneedle drug film tablet is obtained by demolding.

[0012] Optionally, the viscosity of the film-forming liquid is 1000 cps to 200000 cps.

[0013] Optionally, the volume of the film-forming liquid applied in a single application to the sealed container is the sum of the volumes of the multiple film-forming cavities.

[0014] Optionally, the film-forming liquid is extruded from a sealed container into a strip on one side of the top of a disposable mesh plate, and then scraped from one side of the top of the disposable mesh plate to the other side of the top of the disposable mesh plate by a scraper, thus filling the film-forming cavity with the film-forming liquid.

[0015] Optionally, the disposable mesh plate may be made of plastic or metal.

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

[0017] Optionally, after separating the disposable mesh plate, before drying the molding mold, the molding mold is vacuumed with a vacuum degree ≤0.1Mpa and a vacuuming time of 0.5~10min.

[0018] Optionally, during the drying process, multiple molding molds are arranged side by side at intervals from top to bottom, and a unidirectional laminar airflow is formed between the multiple molding molds to dry the drug film forming liquid on the molding molds.

[0019] Optionally, the temperature of the unidirectional laminar airflow is 15-45 degrees Celsius, preferably 20-25 degrees Celsius, and the wind speed is 0.5-2.5 m / s.

[0020] Optionally, a laminar flow drying device is provided for drying. The laminar flow drying device includes a housing, a filter screen, an inlet fan, an exhaust fan, and a material rack. The material rack is located in the housing. The inlet fan and the exhaust fan are located on the front and rear sides of the material rack, respectively. The filter screen is located at the air inlet of the inlet fan. The material rack includes multiple material trays, which are arranged side by side at intervals from top to bottom. Multiple molding dies are placed on the multiple material trays in a corresponding manner. Sealing gaskets are provided between the left and right sides of two adjacent material trays for sealing.

[0021] According to the preparation method of microneedle drug film provided by the present invention, a disposable stencil is used instead of the existing reusable drug film stencil. The disposable stencil is recycled and disposed of after a single coating, eliminating the need for cleaning, thereby effectively improving production efficiency and avoiding the risk of contamination from residual drug film forming liquid on the disposable stencil in subsequent production. On the other hand, during the coating operation, only the drug film forming liquid required for a single coating is applied through a sealed container, effectively avoiding waste of the drug film forming liquid and separating different batches of drug film forming liquid, reducing the risk of contamination. At the same time, encapsulating the drug film forming liquid in a sealed container can effectively prevent solvent evaporation and ensure the quality of the drug film forming liquid. Attached Figure Description

[0022] Figure 1 This is a schematic diagram of the molding die and disposable mesh plate provided by the present invention;

[0023] Figure 2 This is a cross-sectional schematic diagram of the molding die and disposable mesh plate provided by the present invention;

[0024] Figure 3 This is a schematic diagram of the structure of the laminar flow drying device provided by the present invention;

[0025] Figure 4 This is a side view of the laminar flow drying apparatus provided by the present invention;

[0026] Figure 5 yes Figure 4 Enlarged diagram of point A in the middle.

[0027] The reference numerals in the accompanying drawings are as follows:

[0028] 1. Molding mold; 11. Microneedle forming area; 111. Microneedle cavity; 12. Support plate; 2. Disposable mesh plate; 21. Through hole; 3. Drug film forming cavity; 4. Laminar flow drying device; 41. Box body; 42. Air inlet fan; 43. Exhaust fan; 44. Material rack; 441. Material tray; 442. Sealing gasket. Detailed Implementation

[0029] To make the technical problems solved, the technical solutions, and the beneficial effects of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0030] See Figure 1 and Figure 2 As shown, the present invention provides a method for preparing a microneedle drug film, comprising the following steps:

[0031] Multiple microneedle forming areas 11 are provided on the forming mold 1, and multiple microneedle cavities 111 are provided on the surface of the microneedle forming areas 11. Microneedle forming liquid is filled into the multiple microneedle cavities 111 and solidified to obtain the needle body.

[0032] A disposable stencil 2 is detachably placed on the molding mold 1. The disposable stencil 2 has multiple through holes 21 corresponding to the positions of multiple microneedle forming areas 11. The through holes 21 are closed on the surface of the microneedle forming areas 11 to form a drug film forming cavity 3. The drug film forming liquid is encapsulated in a sealed container. The drug film forming liquid required for a single coating is applied to the disposable stencil through the sealed container. The drug film forming liquid is scraped into multiple drug film forming cavities 3 by a scraper.

[0033] The disposable mesh plate 2 is separated from the molding mold 1 and recycled. The drug film forming liquid on the molding mold 1 is dried and solidified to obtain a drug film. The microneedle drug film is obtained by demolding.

[0034] According to the preparation method of microneedle drug film provided by the present invention, a disposable stencil 2 is used instead of the existing reusable drug film mold. The disposable stencil 2 is recycled after a single coating, eliminating the need for cleaning, thereby effectively improving production efficiency and avoiding the risk of contamination from residual drug film forming liquid on the disposable stencil 2 in subsequent production. On the other hand, during the coating operation, only the drug film forming liquid required for a single coating is applied through a sealed container, effectively avoiding waste of the drug film forming liquid and separating different batches of drug film forming liquid, reducing the risk of contamination. At the same time, encapsulating the drug film forming liquid in a sealed container can effectively prevent solvent evaporation and ensure the quality of the drug film forming liquid.

[0035] In some embodiments, the viscosity of the film-forming liquid is 1000 cps to 200000 cps.

[0036] By limiting the viscosity of the film-forming liquid to between 1000 cps and 200000 cps, it is beneficial to apply the film-forming liquid with a scraper, avoiding the problem of non-wetting and shrinkage of the film-forming liquid on the forming mold 1 or disposable screen 2, and improving the scraping effect. If the viscosity of the film-forming liquid is too low, the fluidity of the film-forming liquid on the surface of the forming mold 1 or disposable screen 2 will be too strong, causing it to spread everywhere and making it difficult to meet the scraping conditions.

[0037] In some embodiments, the volume of the film-forming liquid applied in a single application to the sealed container is the sum of the volumes of the plurality of film-forming cavities 3.

[0038] By setting the volume of the film-forming liquid applied in a single application to the sum of the volumes of the multiple film-forming cavities 3, it is possible to effectively ensure that the film-forming liquid used in a single application completely fills the multiple film-forming cavities 3, while also avoiding waste of the film-forming liquid. When separating the disposable mesh plate 2, excessive waste of film-forming liquid is avoided.

[0039] In some embodiments, the film-forming liquid is extruded in strip form from a sealed container onto one side of the top of the disposable mesh plate 2, and then scraped from one side of the top of the disposable mesh plate 2 to the other side of the top of the disposable mesh plate 2 by a scraper, thus filling the film-forming cavity 3 with the film-forming liquid.

[0040] In other embodiments, the drug film forming liquid can also be introduced into the drug film forming cavity 3 by spin coating or other scraping methods.

[0041] In some embodiments, the disposable mesh 2 is made of materials that comply with GMP regulations, such as plastic mesh, metal plate, or wood.

[0042] In a preferred embodiment, the disposable mesh 2 is made of PET mesh or PVC mesh.

[0043] To avoid contamination and waste of the film-forming solution, the amount of film-forming solution applied each time in this invention is just enough to fill multiple film-forming cavities 3 or slightly more. Therefore, if the film-forming solution cannot achieve a good wetting effect with the disposable mesh plate 2, it is prone to non-wetting shrinkage, leading to uneven distribution of the film-forming solution at different positions on the disposable mesh plate 2. Ultimately, this results in insufficient filling of some film-forming cavities 3, and the excess film-forming solution on the disposable mesh plate 2 will contaminate the film-forming solution for the next operation. In this embodiment, PET material is used, which has a good wetting effect with the skeleton material and solvent of the film-forming solution, effectively avoiding the problem of non-wetting shrinkage of the film-forming solution on the disposable mesh plate 2. This facilitates the scraping operation of the film-forming solution by the scraper, ensuring that the film-forming solution is introduced into multiple film-forming cavities 3. Using other materials, such as metal mesh plates, the problem of non-wetting shrinkage of the film-forming solution on the disposable mesh plate 2 is more likely to occur.

[0044] When the microneedle forming area 11 is made of a rigid material, the tip of the microneedle is prone to breakage due to stress during demolding because rigid materials are difficult to deform. This results in the microneedle not having good penetration performance, and the broken microneedle also affects the preparation of the next batch of microneedle patches. In a preferred embodiment, the microneedle forming area 11 is made of a flexible material. Compared with rigid materials, flexible materials have deformable characteristics, which is beneficial to provide an extremely gentle demolding process and can reduce the compressive stress on the microneedle cavity 111 during the demolding process. However, due to the deformability of the flexible material, shrinkage will occur during the curing process of the microneedle and the substrate, which will cause the microneedle forming area 11 to deform, which is also not conducive to the microneedle forming effect and demolding.

[0045] In some embodiments, the molding die 1 includes a support plate 12 and a plurality of microneedle forming areas 11. The shape of the microneedle forming areas 11 is consistent with the shape of the drug film to be prepared. The plurality of microneedle forming areas 11 are spaced apart and embedded on the support plate 12. The support plate 12 is a rigid material and the microneedle forming areas 11 are flexible and breathable materials.

[0046] In some embodiments, the rigid material is selected from monocrystalline silicon, stainless steel, aluminum plate, titanium plate, silicate glass, quartz glass, ceramics, polytetrafluoroethylene, polyetheretherketone (PEEK), pyridine propanesulfonate, etc., and the flexible material is selected from siloxanes.

[0047] In this embodiment, a molding die 1 is prepared by combining flexible and rigid materials. The microneedle forming 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 supporting and fixing function for the microneedle forming area 11, which is used to maintain the stability of the shape of the microneedle forming area 11. The microneedle cavity 111 provided on the microneedle forming area 11 is used for the curing and molding of microneedles. The use of flexible materials helps to reduce the stress on the microneedles during demolding and improve the integrity of the microneedles after demolding. At the same time, by fixing the shape of the microneedle forming area 11 by the support plate 12 of the rigid material, deformation of the microneedle forming area 11 during the curing and shrinkage of the microneedle forming liquid can be avoided, thereby effectively improving the molding effect and demolding integrity of the microneedles.

[0048] In some embodiments, the microneedle cavity 111 is a pointed cone-shaped cavity with its tip facing the interior of the microneedle forming area 11, such as a round cone, an elliptical cone, a regular polygonal cone, an irregular polygonal cone, etc.

[0049] In some embodiments, the depth of the microneedle cavity 111 is 0.001 μm-1000 μm, and the maximum diameter is 0.005-3000 μm. Meanwhile, to ensure a certain density of the microneedle array, the distance between the microneedle cavities 111 is 4 μm-1000 μm.

[0050] In some embodiments, after separating the disposable mesh plate 2, before drying the molding mold 1, the molding mold 1 is subjected to vacuum treatment with a vacuum degree ≥0.1Mpa and a vacuum suction time of 0.5~10min.

[0051] Vacuuming helps to remove air bubbles from the microneedle cavity 111 and the drug film forming cavity 3, thus avoiding the impact of residual air bubbles on the strength of the microneedle and the integrity of the drug film.

[0052] In some embodiments, during the drying process, multiple molding molds 1 are arranged side by side at intervals from top to bottom, and a unidirectional laminar airflow is formed between the multiple molding molds 1 to dry the drug film forming liquid on the molding molds 1.

[0053] By setting multiple molding molds 1 at intervals on the top and bottom for unidirectional laminar flow drying, on the one hand, the space utilization rate is improved and the space occupied by the drying device is effectively reduced; on the other hand, the consistency of drying quality at different positions on the drug film is improved, avoiding white spots or cracks, and improving drying efficiency.

[0054] In some embodiments, the temperature of the unidirectional laminar airflow is 15-45 degrees Celsius, with better drying effect at 20-25 degrees Celsius, and the air velocity is 0.5-2.5 m / s.

[0055] By controlling the temperature and velocity of the unidirectional laminar airflow, the drying rate can be slightly increased while ensuring drying quality, thereby increasing production capacity.

[0056] like Figures 3-5 As shown, in some embodiments, a laminar flow drying device 4 is provided for drying. The laminar flow drying device 4 includes a housing 41, a filter screen, an inlet fan 42, an exhaust fan 43, and a material rack 44. The material rack 44 is located in the housing 41. The inlet fan 42 and the exhaust fan 43 are located on the front and rear sides of the material rack 44, respectively. The filter screen is located at the air inlet of the inlet fan 42. The material rack 44 includes multiple material trays 441, which are arranged side by side at intervals from top to bottom. Multiple molding dies 1 are placed on the multiple material trays 441 in a one-to-one correspondence. Sealing gaskets 442 are provided between the left and right sides of two adjacent material trays 441 for sealing, so that the air generated by the inlet fan 42 and the exhaust fan 43 can only flow in the front and back direction between the two material trays 441, thereby forming a stable laminar flow and achieving a better drying effect.

[0057] In some embodiments, the sealing gasket 442 is a silicone gasket.

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a microneedle drug film, characterized in that, Includes the following operations: Multiple microneedle forming areas are provided on the forming mold. The forming mold includes a support plate and multiple microneedle forming areas. The shape of the microneedle forming areas is consistent with the shape of the drug film to be prepared. Multiple microneedle forming areas are embedded in the support plate at intervals. The support plate is made of rigid material, and the microneedle forming areas are made of flexible and breathable material. Multiple microneedle cavities are provided on the surface of the microneedle forming areas. Microneedle forming liquid is filled into the multiple microneedle cavities and solidified to obtain the needle body. A disposable stencil is detachably placed on the molding die. The disposable stencil has multiple through holes corresponding to the positions of multiple microneedle forming areas. The through holes are sealed on the surface of the microneedle forming areas to form a drug film forming cavity. The drug film forming liquid is encapsulated in a sealed container. The drug film forming liquid required for a single coating is applied to the disposable stencil through the sealed container. The drug film forming liquid is scraped onto multiple drug film forming cavities by a scraper. The viscosity of the drug film forming liquid is 1000cps~200000cps. The disposable stencil is made of PET stencil. The disposable mesh plate is separated from the molding die and recycled. The drug film forming liquid on the molding die is dried and solidified to obtain a drug film. The microneedle drug film tablets are obtained by demolding.

2. The method for preparing the microneedle drug film according to claim 1, characterized in that, The volume of the film-forming liquid applied in a single application to the sealed container is the sum of the volumes of the multiple film-forming cavities.

3. The method for preparing the microneedle drug film according to claim 1, characterized in that, The film-forming liquid is extruded in strips from the top of a disposable mesh plate from a sealed container. The film-forming liquid is then scraped from one side of the top of the disposable mesh plate to the other side using a scraper, thus filling the film-forming cavity.

4. The method for preparing the microneedle drug film according to claim 1, characterized in that, After separating the disposable mesh, before drying the molding mold, the molding mold is vacuumed with a vacuum degree ≤0.1Mpa and a vacuuming time of 0.5~10min.

5. The method for preparing the microneedle drug film according to claim 1, characterized in that, During the drying process, multiple molding molds are arranged side by side at intervals from top to bottom, and a unidirectional laminar airflow is formed between the multiple molding molds to dry the drug film forming liquid on the molding molds.

6. The method for preparing the microneedle drug film according to claim 5, characterized in that, The temperature of the unidirectional laminar airflow is 15-45 degrees Celsius, and the wind speed is 0.5-2.5 m / s.

7. The method for preparing the microneedle drug film according to claim 5, characterized in that, A laminar flow drying device is provided for drying. The laminar flow drying device includes a box, a filter screen, an inlet fan, an exhaust fan, and a material rack. The material rack is located in the box. The inlet fan and the exhaust fan are located on the front and rear sides of the material rack, respectively. The filter screen is located at the air inlet of the inlet fan. The material rack includes multiple material trays, which are arranged side by side at intervals from top to bottom. Multiple molding dies are placed on the multiple material trays one by one. Sealing gaskets are provided between the left and right sides of two adjacent material trays for sealing.

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