A micro-needle device preparation method based on stepped casting and functional film integration

Abstract

The application discloses a kind of based on stepped casting and function film integrated microneedle device preparation method, belong to medical instrument manufacturing technical field.The method includes: through stepped casting, drug-containing microneedle needle body layer and backing layer are prepared in turn;A piece of functional film is integrated on the backing layer;Selected function device is fixed on the outer surface of the functional film by fixing agent;Finally, the microneedle device is obtained by demolding.The core of the application is to introduce a piece of functional film layer, not only effectively block the pollution of liquid fixing agent to drug layer, but also inhibit the reverse diffusion of drug molecules, thereby significantly improving the bioavailability of drug.More importantly, with the flexibility of the integrated method of the functional film, the application realizes the wide compatibility of microneedle and photoelectric chip, sensor, micro energy device and micro vibration motor and other various functional devices, fundamentally solves the problem of poor universality of existing process.The application provides a kind of efficient, reliable and highly universal microneedle device preparation method.

Description

Technical Field

[0001] This invention relates to the field of medical device manufacturing technology, and in particular to a method for manufacturing microneedle devices, specifically a method for manufacturing microneedle devices based on a stepped casting method and a functional thin film integration method. Background Technology

[0002] Microneedle transdermal drug delivery technology has broad application prospects in the field of drug delivery due to its advantages such as being painless and minimally invasive. In recent years, in order to improve treatment efficacy, researchers have begun to explore innovative solutions that combine microneedles with functional devices.

[0003] In existing technologies, the integration of microneedles and devices mainly employs a direct fixation method. Specifically, the microneedle body and backing layer are first prepared by stepped casting, and after curing, the functional device is directly fixed to the backing surface using an adhesive. Chinese patent application CN202211251050.8, which discloses "A Flexible Microneedle Patch for Photodynamic Therapy and its Preparation Method," utilizes this method.

[0004] The existing technical solutions face two technical challenges during implementation: First, the liquid adhesive used in the device fixation process is prone to leaking from the backing area to the microneedle body, causing drug contamination; second, during the preparation of the backing layer, the drug in the needle body layer will spontaneously diffuse to the upper layer, resulting in reduced drug utilization; third, existing processes are mostly designed for specific devices and lack a universal preparation method that can be widely compatible with different types, materials and functions of devices.

[0005] This invention innovatively proposes a functional thin film integration method and combines it with a stepped casting method to form a novel method for manufacturing microneedle devices, effectively solving the technical problems of fixative contamination and drug diffusion. Summary of the Invention

[0006] The purpose of this invention is to overcome the technical difficulties in the existing microneedle device fabrication, such as liquid fixative contamination of microneedle drugs, drug diffusion into the backing layer, and limited applicability of the method, and to provide a microneedle device manufacturing method based on the stepped casting method and the functional thin film integration method.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0008] A method for fabricating microneedle devices based on stepped casting and functional thin film integration includes the following steps:

[0009] (1) Preparation of microneedle body layer: The drug-containing microneedle body solution is poured into the microneedle mold, and after vacuum degassing and scraping off excess solution, it is dried to form a solidified microneedle body array;

[0010] (2) Preparation of backing layer: The backing solution is poured into the mold in which the needle array has been formed, and after vacuum degassing, it is dried to form a backing layer that is bonded to the needle array.

[0011] (3) Integrated functional film: An adhesive layer is constructed on the surface of the backing layer, and then a functional film is integrated thereon; the functional film serves as a core barrier and adapter structure to isolate subsequent process contaminants and inhibit drug back diffusion;

[0012] (4) Integrating functional devices: fixing the functional devices to the outer surface of the functional film using an adhesive;

[0013] (5) Demolding: Remove the complete structure from the mold to obtain the microneedle device.

[0014] Preferably, the thickness of the functional film is 10~500μm, and its Young's modulus is adjustable in the range of 0.1~3 GPa.

[0015] Preferably, the functional film is a breathable functional layer with a microporous structure, and its water vapor permeability is not less than 300 g / (m²·24h).

[0016] Preferably, the surface of the functional film is subjected to plasma treatment or chemical modification to enhance its interfacial adhesion or to endow it with specific functions.

[0017] Preferably, the adhesive layer is formed from water, ethanol, biocompatible adhesive, pressure-sensitive adhesive, or a material that can be activated by light or heat.

[0018] Preferably, the material of the functional film is selected from polydimethylsiloxane, polyurethane, cyclic olefin polymer, polyethylene terephthalate, polyimide, or blended composite materials.

[0019] Preferably, the adhesive is a UV-curable adhesive, a visible-light curable adhesive, a thermosetting adhesive, a moisture-curable adhesive, or a two-component reactive adhesive.

[0020] Preferably, the step of integrating functional devices needs to be carried out in a local vacuum or inert atmosphere environment to ensure that the bonding interface is free of bubbles and the bonding is strong.

[0021] Preferably, the functional devices include, but are not limited to, optoelectronic chips, various sensors, micro-energy devices, micro-pumps, or combined modules thereof.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) After the introduction of the functional film, the liquid fixative can be effectively blocked from penetrating into the microneedle body layer, thereby avoiding drug contamination;

[0024] (2) The introduction of functional films blocks the path of drug molecules in the microneedle body layer to diffuse to the upper layer (i.e., the backing layer and the device layer), so that more drugs are retained in the needle body and the bioavailability of drugs is improved.

[0025] (3) By actively designing and controlling the material, mechanical properties and surface properties of functional thin films, this invention can stably and reliably integrate a variety of functional devices, from rigid semiconductor chips to flexible stretchable circuits, and realize the generalization of the process.

[0026] (4) Optimized interface treatment and bonding process ensure high bonding strength and good long-term stability between functional thin film and functional device, thus improving the overall performance of the product. Attached Figure Description

[0027] Figure 1 This is a schematic diagram of the preparation method of the present invention;

[0028] Figure 2 This is a schematic diagram of the overall structure of the present invention;

[0029] Figure 3 This is an exploded structural diagram of the present invention.

[0030] Figure 4 This is a schematic diagram of the overall structure of a blue light chip microneedle patch carrying total flavonoids from Drynaria fortunei.

[0031] Figure 5 This is an exploded structural diagram of a blue light chip microneedle patch carrying total flavonoids from Drynaria fortunei.

[0032] Figure 6 This is a schematic diagram of the overall structure of a microneedle patch for a micro-generator carrying quercetin.

[0033] Figure 7 This is a schematic diagram of the exploded structure of a microneedle patch for a micro-generator carrying quercetin.

[0034] Figure 8 This is a schematic diagram of the overall structure of a vibrating microneedle patch carrying total glycosides of Panax notoginseng.

[0035] Figure 9 This is a schematic diagram of the exploded structure of a vibrating microneedle patch carrying total glycosides of Panax notoginseng.

[0036] In the figure: 1. Microneedle body, 2. Microneedle backing layer, 3. Functional film, 4. Curing layer, 5. Device, 6. Microneedle body loaded with total flavonoids from Drynaria fortunei, 7. Microneedle backing layer, 8. PDMS film, 9. UV curing layer, 10. Blue light chip, 11. Microneedle body loaded with quercetin, 12. Microneedle backing layer, 13. Polyurethane film, 14. Epoxy resin curing layer, 15. Microgenerator, 16. Microneedle body loaded with total glycosides of Panax notoginseng, 17. Microneedle backing layer, 18. Cycloolefin polymer film, 19. Silicone curing layer, 20. Micro vibration motor. Detailed Implementation

[0037] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0038] like Figures 1 to 3 As shown, this invention provides a method for manufacturing microneedle devices based on stepped casting and functional thin film integration, which can be implemented through the following specific operations:

[0039] (1) Prepare and pour the microneedle body layer 1

[0040] First, a microneedle matrix material containing therapeutic or functional drugs, such as an aqueous solution or mixture of hyaluronic acid or polyvinylpyrrolidone, is poured into the cavity of a microneedle mold. Next, the mold is transferred to a vacuum drying oven for degassing to remove air bubbles from the needle tips and ensure complete needle formation. Then, excess treatment solution is scraped off the mold surface with a scraper, leaving only the portion inside the cavity. Finally, the mold is placed in a drying oven for preliminary drying, forming a cured microneedle array.

[0041] (2) Forming a backing layer 2

[0042] After the microneedle body layer has cured, a backing layer solution, such as an aqueous solution of polyvinyl alcohol or sodium carboxymethyl cellulose, is poured into a mold to uniformly cover the substrate of the microneedle body layer. A second vacuum degassing process is then performed to ensure the backing layer is fully filled and free of air bubbles. A second drying and curing process is then carried out to form a backing layer 2 that is tightly bonded to the microneedle array.

[0043] (3) Integrated functional thin film 3

[0044] A thin layer of adhesive is applied to the fully cured backing layer 2. Then, the pre-fabricated functional film 3 is smoothly attached to it, and light pressure is applied to complete the adhesion and curing. The isolation layer formed in this step is a key structure that blocks subsequent fixatives and prevents drug diffusion. For applications with high reliability requirements, the bonding surface between the functional film 3 and the backing layer 2 can be pretreated with plasma to significantly improve the adhesion between the layers.

[0045] (4) Integrated functional devices 5

[0046] Selected functional devices 5, such as optoelectronic chips, various sensors, micro-energy devices, micro-pumps, or combinations thereof, are coated with a suitable adhesive on their backsides, then precisely aligned and pressed onto the outer surface of the functional film. This pressing step is preferably performed in a vacuum chamber to eliminate interfacial air and ensure a uniform, bubble-free adhesive layer. Subsequently, curing is triggered according to the type of adhesive, firmly fixing the functional device onto the microneedle patch, forming a cured layer 4.

[0047] (5) Demolding to obtain the final product

[0048] After all layers have fully cured, carefully peel the complete structure from the microneedle mold. The overall structure and exploded structure can be referenced separately. Figure 2 , 3 .

[0049] The height of the microneedles in the microneedle array is 50–1500 μm.

[0050] The thickness of the functional thin film 3 is 10–500 μm.

[0051] Furthermore, to ensure the barrier effect against liquid adhesives, the surface energy of the functional film needs to be controlled within a specific range. Preferably, the functional film has a contact angle greater than 90° with acrylate UV-curable adhesives, exhibiting excellent non-wettability, thereby physically blocking the penetration of liquid colloids.

[0052] Furthermore, in order to ensure interfacial compatibility with the backing layer, the surface tension of the functional film after plasma treatment must be greater than 45 mN / m to ensure a strong interfacial bond with the hydrophilic backing material, and the peel strength must be no less than 0.5 N / mm.

[0053] The adhesive is water, ethanol, a biocompatible adhesive, or a material that generates adhesiveness through physical activation.

[0054] The functional film 3 is a light-transmitting film, and its material is selected from one of polydimethylsiloxane, polyurethane or cyclic olefin polymer.

[0055] The adhesive is a UV-curable adhesive, a visible-light curable adhesive, a thermosetting adhesive, or a two-component mixed curable adhesive.

[0056] Material properties and barrier mechanism of functional thin films: In this invention, the core function of the functional thin film 3 is to construct a dual barrier layer of physical and chemical barrier.

[0057] Addressing the barrier effect of liquid curing agents: To solve the problem of liquid curing agents penetrating downwards and contaminating the drug, this invention preferably uses low surface energy materials or highly crystalline polymers. These materials have extremely low wettability to acrylate adhesives, ensuring that the liquid adhesive cannot penetrate the film, thereby perfectly protecting the underlying drug layer.

[0058] Addressing the issue of drug molecule obstruction: To solve the problem of upward and backward diffusion of drug molecules (especially large molecular drugs with molecular weights in the range of 500 Da to 50 kDa, such as peptides and proteins), this invention utilizes the dense molecular chain arrangement structure of the aforementioned materials to physically block the diffusion path of drug molecules, thereby significantly improving the bioavailability of drugs.

[0059] Complexity control: Although this invention introduces a functional thin film layer, it does not significantly increase the complexity of the process. This invention innovatively employs a "dry transfer bonding" process.

[0060] The functional film is an industrial-grade prefabricated standard sheet that does not require on-site synthesis and can be used with just simple punching, resulting in extremely low material costs.

[0061] In step (3), water, ethanol, or medical pressure-sensitive adhesive is used as a temporary adhesive layer, and the film can be quickly integrated through simple rolling. Compared with the existing technology that requires precise control of the leveling and curing of liquid adhesive, the dry process of the present invention has a wider process window, is simpler to operate, and avoids the risk of expensive drug layers being scrapped due to adhesive overflow, resulting in better overall yield and economy.

[0062] Mechanical stability of the multi-layer structure: To ensure the interfacial stability of the multi-layer heterogeneous structure of "functional device-functional film-backing layer" during microneedle insertion and use, this invention incorporates a special mechanical design:

[0063] Example 1

[0064] This embodiment provides a blue light chip microneedle patch carrying total flavonoids from Drynaria fortunei, the structure of which is as follows: Figure 4 and Figure 5 As shown, it includes a microneedle body 6 carrying total flavonoids from Drynaria fortunei, a microneedle backing layer 7, a PDMS film 8, an ultraviolet curing layer 9, and a blue light chip 10.

[0065] The preparation method of this microneedle patch includes the following steps:

[0066] (1) Preparation of microneedle body layer: 200 μL of hyaluronic acid aqueous solution and 50 μL of total flavonoid solution of Drynaria fortunei were mixed evenly and coated on the surface of the microneedle mold. Then, the mold was placed in a vacuum drying oven for vacuum degassing. Excess needle matrix was scraped off from the surface of the microneedle mold and dried in a drying oven at 37°C for 15 min until the microneedle body 6 was completely dry;

[0067] (2) Preparation of backing layer: Take 400 μL of polyvinyl alcohol aqueous solution and coat it on the backing layer of the microneedle mold. Then, perform vacuum degassing treatment again and place it in a drying oven at 37℃ for 14 h until the microneedle backing layer 7 is completely cured.

[0068] (3) Integrated functional film: Spray 20 μL of deionized water onto the microneedle backing, fix the PDMS film 8 onto the microneedle backing, and then dry it in a drying oven at 37°C for 40 min.

[0069] (4) Integrating functional devices: Apply a small amount of UV curing adhesive 9 to the blue light chip 10 and cure it in a vacuum environment using a roller-to-flatbed UV imprinter for 60 seconds until the blue light chip 10 is fixed on the micro-needle patch, and at the same time, a UV curing layer 9 is formed.

[0070] (5) Demolding: Demolding the microneedle array from the mold to obtain an integrated microneedle patch, such as... Figure 4 , 5 As shown.

[0071] Example 2

[0072] This embodiment provides a microneedle patch for a micro-generator loaded with quercetin, the structure of which is as follows: Figure 6 and Figure 7 As shown, it includes a microneedle body 11 carrying quercetin, a microneedle backing layer 12, a polyurethane film 13, an epoxy resin curing layer 14, and a microgenerator 15.

[0073] The preparation method of this microneedle patch includes the following steps:

[0074] (1) Preparation of microneedle body layer: 200 μL of polyvinylpyrrolidone aqueous solution and 50 μL of quercetin solution were mixed evenly and coated on the surface of the microneedle mold. Then, the mold was placed in a vacuum drying oven for vacuum degassing. Excess needle matrix was scraped off from the surface of the microneedle mold and dried in a drying oven at 37°C for 15 min until the microneedle body 11 was completely dry;

[0075] (2) Preparation of backing layer: Take 400 μL of sodium carboxymethyl cellulose aqueous solution and coat it on the backing layer of the microneedle mold. Then, perform vacuum degassing treatment again and place it in a drying oven at 37℃ for 14 h until the microneedle backing layer 12 is completely cured.

[0076] (3) Integrated functional film: Spray 20 μL of ethanol solution onto the backing of the microneedle, fix the polyurethane film 13 onto the backing of the microneedle, and then dry it in a drying oven at 37°C for 40 min.

[0077] (4) Integrating functional devices: The micro generator 15 is dipped in a small amount of epoxy resin adhesive and fixed on the surface of the functional film. It is then cured at 37°C to form an epoxy resin cured layer 14.

[0078] (5) Demolding: Demolding the microneedle array from the mold to obtain an integrated microneedle patch, such as... Figure 6 , 7 As shown.

[0079] Example 3

[0080] This embodiment provides a vibrating microneedle patch loaded with total glycosides of Panax notoginseng, the structure of which is as follows: Figure 8 and Figure 9 As shown, it includes a microneedle body 16 carrying total glycosides of Panax notoginseng, a microneedle backing layer 17, a cyclic olefin polymer film 18, a silicone curing layer 19, and a micro vibration motor 20.

[0081] The preparation method of this microneedle patch includes the following steps:

[0082] (1) Preparation of microneedle body layer: 200 μL of sodium alginate aqueous solution and 50 μL of Panax notoginseng total glycosides aqueous solution were mixed evenly and coated on the surface of the microneedle mold. Then, the mold was placed in a vacuum drying oven for vacuum degassing. Excess needle body matrix was scraped off from the surface of the microneedle mold and dried in a drying oven at 35°C for 20 min until the microneedle body 16 was completely dry;

[0083] (2) Preparation of backing layer: Take 400 μL of gelatin aqueous solution and apply it to the backing layer of the microneedle mold. Perform vacuum degassing treatment again, and then place it in a drying oven at 35°C for 12 h until the microneedle backing layer 17 is completely cured.

[0084] (3) Integrated functional film: 20 medical pressure-sensitive adhesive is coated on the backing of the microneedle, and the cyclic olefin polymer film 18 is fixed on the backing of the microneedle, and then cured at room temperature for 30 min.

[0085] (4) Integrated functional device: A small amount of silicone is coated on the back of the micro vibration motor 20 and fixed on the surface of the cyclic olefin polymer film 18. It is cured at 60°C for 40 min to form a silicone curing layer 19.

[0086] (5) Demolding: Demolding the microneedle array from the mold to obtain an integrated vibrating microneedle patch, such as Figure 8 , 9 As shown.

[0087] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for fabricating microneedle devices based on stepped casting and functional thin film integration, characterized in that, Includes the following steps: Step (1), prepare the microneedle body layer; pour the drug-containing microneedle body solution into the microneedle mold, and after vacuum degassing, scraping off the excess solution and drying, a solidified microneedle body array is formed; Step (2), prepare the backing layer; pour the backing solution into the mold in which the needle array has been formed, and after vacuum degassing and drying, form a backing layer that is bonded to the needle array; Step (3), integrate the functional film; form an adhesive layer on the surface of the backing layer, and then integrate a functional film thereon; The functional film is made of low surface energy material or high crystallinity polymer with a Young's modulus of 0.1 to 3 GPa, and is used to block the penetration of liquid fixatives and the reverse diffusion of drug molecules. Step (4), integrate the functional device; fix a functional device to the outer surface of the functional film away from the backing layer using an adhesive; Step (5), demolding; the composite structure obtained in step (4) is removed from the microneedle mold to obtain a microneedle patch integrating functional devices.

2. The method according to claim 1, characterized in that, The material of the functional film is selected from one of polydimethylsiloxane, cyclic olefin polymer, fluoropolymer or polyurethane.

3. The method according to claim 1, characterized in that, The surface of the functional film is subjected to plasma treatment or chemical modification to introduce hydroxyl or carboxyl polar groups to enhance the hydrogen bonding force with the backing layer.

4. The method according to claim 1, characterized in that, The adhesive layer is formed from water, ethanol, medical pressure-sensitive adhesive or thermosetting silicone; the Young's modulus of the functional film is between the modulus of the backing layer and the modulus of the functional device, forming a gradient modulus transition structure to alleviate interfacial stress. The functional film is a prefabricated standard sheet. In step (3), the functional film is integrated onto the backing layer using a dry transfer bonding process.

5. The method according to claim 1, characterized in that, The thickness of the functional film is 10–500 μm; the adhesive layer is formed from water, ethanol, biocompatible adhesive, pressure-sensitive adhesive, or materials that can be activated by light or heat.

6. The method according to claim 1, characterized in that, The adhesive is a UV-curable adhesive, a visible-light-curable adhesive, a thermosetting adhesive, a moisture-curable adhesive, or a two-component reactive adhesive.

7. The method according to claim 1, characterized in that, Step (4) is carried out in a local vacuum or inert atmosphere environment.

8. The method according to claim 1, characterized in that, The functional device includes at least one of a photoelectric chip, a sensor, a micro-energy device, a micro-pump, and a micro-vibration motor; the height of the microneedle array is 50–1500 μm.

9. The method according to claim 1, characterized in that, The drug includes at least one of the following: total flavonoids from Drynaria fortunei, quercetin, total glycosides of Panax notoginseng, small molecule drugs, peptides, proteins, nucleic acids, or vaccines.

10. A microneedle patch prepared by the method according to any one of claims 1-9, characterized in that, include: The microneedle needle layer contains the drug; A backing layer is disposed at the base of the microneedle body layer and provides support thereto; The functional film layer is fixed to the side of the backing layer away from the microneedle body layer by an adhesive layer; The functional device is fixed to the outer surface of the functional thin film layer away from the backing layer by an adhesive.

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