Microneedle mold and microneedle forming method

Abstract

The application belongs to the technical field of medical equipment, and particularly discloses a microneedle mold and a microneedle forming method, which comprises an upper mold and a lower mold arranged in a mold fixing assembly; the mold fixing assembly comprises a mold base and vertical plates arranged on both sides of the mold base, and the upper mold and the lower mold are respectively in sliding connection with the vertical plates; a plurality of first microneedle forming holes are arranged in the upper mold, and a plurality of second microneedle forming holes are arranged in the lower mold, the first microneedle forming holes are in a circular truncated cone structure, the second microneedle forming holes are in a conical structure, the bottom of the second microneedle forming holes is in a closed state under normal pressure, and a microneedle material channel is formed under a pressure state. The application further discloses a method for preparing a microneedle array by using the microneedle mold, in the process of preparing the microneedle, the microneedle material is filled into the mold by pressure driving, residual bubbles in the bottom are discharged through the channel, no bubbles are generated in the pouring process, and no centrifugal or vacuum process is needed, so that the production efficiency is improved.

Description

Technical Field

[0001] This invention belongs to the field of medical device technology, and specifically relates to a microneedle mold and a microneedle forming method. Background Technology

[0002] Microneedle-based painless transdermal drug delivery, as a novel drug delivery technology, can target and penetrate the stratum corneum barrier to form tiny drug delivery channels, improving the efficiency of transdermal drug delivery. It can also be administered by the user, is safe and painless, and represents the future direction of drug delivery through the skin into the body.

[0003] Existing microneedle fabrication methods often employ casting processes. However, during casting, numerous air bubbles form inside the mold, requiring centrifugation or vacuuming to remove them. For instance, Chinese patent CN109693323A discloses a microneedle mold, a mold itself, and a method for forming the microneedle mold. This method connects a drainage channel to a negative pressure generator. During microneedle formation, the negative pressure generator applies negative pressure to the drainage channel, allowing any air bubbles that may be generated within the microneedle to escape. This approach is relatively easy to remove air bubbles at the bottom of the mold, but removing bubbles from the middle or upper parts of the mold is more difficult. Furthermore, during microneedle fabrication, the microneedle tip needs to be as small as possible to quickly penetrate the stratum corneum for drug delivery. However, existing microneedle molds, if using small-sized microneedle models, pose a risk of tip clogging. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of existing technology, such as difficulty in removing air bubbles and easy clogging during the casting process, and to provide a microneedle mold and microneedle forming method.

[0005] In a first aspect, the present invention provides a microneedle mold, comprising an upper mold and a lower mold disposed inside a mold fixing assembly, wherein the upper mold is a rigid structure and the lower mold is a flexible structure;

[0006] The mold fixing assembly includes a mold base and upright plates disposed on both sides of the mold base, wherein the upper mold and the lower mold are slidably connected to the upright plates respectively;

[0007] The upper mold has a plurality of first microneedle forming holes inside, and the lower mold has a plurality of second microneedle forming holes inside. The number and position of the first and second microneedle forming holes are adapted to each other. The first microneedle forming holes are frustum structures, and the second microneedle forming holes are conical structures. The bottom of the second microneedle forming holes is closed under normal pressure and forms a microneedle material channel under pressure. The bottom inner diameter of the frustum structure is the same as the top inner diameter of the conical structure, and the slopes of the frustum structure and the conical structure are the same.

[0008] The bottom of the lower template is provided with a tray, which is detachably connected to the mold base.

[0009] A further embodiment is that a cover plate is provided on the top of the upper mold, and the cover plate is detachably and sealingly connected to the upper mold;

[0010] A pressure chamber is formed between the cover plate and the first microneedle forming hole. A through hole is provided at the center of the top of the cover plate. A high-pressure hose is installed in the through hole. One end of the high-pressure hose passes through the through hole and communicates with the pressure chamber. The other end of the high-pressure hose is connected to an external micro air pump for introducing high-pressure gas into the pressure chamber to pressurize the microneedle material poured into the upper mold. This allows the microneedle material to enter the tray under pressure through the microneedle material channel at the bottom of the conical structure.

[0011] A further embodiment is that the tray is provided with a volume groove inside that is adapted to the number and position of the second microneedle forming holes, for receiving microneedle material from the microneedle material channel;

[0012] A sensor is provided at the bottom of the volumetric groove, and the microneedle mold also includes a controller, which is connected to the sensor and an external micro air pump respectively.

[0013] The controller is used to acquire the parameters of the sensor and generate a power signal to control the micro air pump based on the threshold and control strategy built into the controller, so as to control the flow rate of the micro needle material.

[0014] A further embodiment is that both sides of the upper mold and the lower mold are provided with sliders, and the sliders are also provided with positioning devices for fixing the sliders;

[0015] The inner side of the upright plate is provided with a slide rail adapted to the slider, and the slider is slidably connected to the slide rail.

[0016] A further embodiment is that the lower mold is a recessed structure, the bottom of the upper mold is provided with a snap-fit ​​boss, and the outer edge of the snap-fit ​​boss is provided with a sealing strip. When the upper mold and the lower mold are fitted together, the outer side of the sealing strip and the inner wall of the lower mold form a sealing surface.

[0017] A further embodiment involves coating the inner walls of both the first and second microneedle forming holes with a release agent.

[0018] A second aspect of the present invention provides a microneedle molding method applied to the aforementioned microneedle mold, comprising the following steps:

[0019] Adjust the positions of the upper and lower molds, and use a positioning device to fix the position of the slider so that the upper and lower molds fit tightly together;

[0020] Pour a certain amount of microneedle material into the upper part of the mold and let it flow naturally.

[0021] Install the cover plate on the top of the upper mold to form a pressure chamber inside the upper mold. Start the air pump to pressurize. Under the pressure, the material is pressed into the first micro-needle forming hole, the second micro-needle forming hole, and the inside of the tray in sequence.

[0022] The controller monitors sensor data in real time and generates a power signal to control the micro air pump based on the built-in threshold and control strategy, so as to control the flow rate of the micro needle material. When the micro needle material flows out in a columnar and uniform manner, the controller controls the micro air pump to stop pressurizing.

[0023] Vacuum drying is performed while keeping the upper and lower molds in a fitted state.

[0024] After drying, the microneedle array is obtained by demolding.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] (1) The microneedle mold of the present invention includes an upper mold and a lower mold. While improving the demolding rate, the lower mold adopts a flexible structure and has a microneedle material channel at the bottom. The microneedle material is filled into the mold by pressure, and residual air bubbles at the bottom are discharged through the microneedle material channel. Therefore, no air bubbles are generated during the casting process, no centrifugation or vacuum process is required, and no blockage is caused, thus improving production efficiency. Furthermore, the flexible structure of the lower mold provides the necessary conditions for miniaturizing the microneedle tip.

[0027] (2) The present invention places the upper mold and the lower mold inside the mold fixing component and slides to connect with the mold fixing component. When the upper and lower molds are attached, the upper mold only needs to slide on the upright plate, which also ensures the accuracy of the upper and lower molds being attached.

[0028] (3) The present invention has a sensor at the bottom of the volume tank. The controller monitors the parameters of the sensor in real time and forms a power signal to control the micro air pump based on the built-in threshold and control strategy of the controller, so as to control the flow rate of the micro needle material. When the parameters of each sensor reach the first threshold, the controller adjusts the output power of the micro air pump. When the parameters of each sensor reach the second threshold, the controller controls the micro air pump to stop working. Attached Figure Description

[0029] The following figures are for illustrative purposes only and are not intended to limit the scope of the invention, wherein:

[0030] Figure 1 : Schematic diagram of the structure of the present invention;

[0031] Figure 2 : Schematic diagram of the internal structure of the upper and lower molds;

[0032] Figure 3 : Schematic diagram of the usage state of this invention;

[0033] Figure 4 : Pallet structure diagram;

[0034] Figure 5 Field emission scanning electron microscope images of PDMS materials, where A is PDMS; B is UVO / PDMS; C is 20% 2-BMT / PDMS; and D is 20% 2-BMT / UVO / PDMS.

[0035] In the diagram: 1. Mold base; 2. Vertical plate; 3. Upper mold; 4. Lower mold; 5. Tray; 6. Cover plate; 7. High pressure pipe; 8. Slide rail; 9. Slider; 10. Snap-fit ​​boss; 11. First microneedle forming hole; 12. Second microneedle forming hole; 13. Pressure chamber; 14. Volumetric groove; 15. Sensor. Detailed Implementation

[0036] To make the objectives, technical solutions, design methods, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention.

[0037] Example 1

[0038] like Figure 1 and Figure 2 As shown, the present invention provides a microneedle mold, including an upper mold 3 and a lower mold 4 disposed inside a mold fixing assembly. The upper mold 3 is a rigid structure, and the lower mold 4 is a flexible structure. The mold fixing assembly includes a mold base 1 and upright plates 2 disposed on both sides of the mold base 1. Slider 9 is disposed on both sides of the upper mold 3 and the lower mold 4. The slider 9 is also provided with a positioning device for fixing the slider 9. The inner side of the upright plate 2 is provided with a slide rail 8 adapted to the slider 9, and the slider 9 is slidably connected to the slide rail 8.

[0039] The upper mold 3 has a plurality of first microneedle forming holes 11 arranged in a rectangular array inside, and the lower mold 4 has a plurality of second microneedle forming holes 12 inside, such as... Figure 3As shown, when the upper mold 3 and the lower mold 4 are in contact, the bottom of the first microneedle forming hole 11 and the top of the second microneedle forming hole 12 are completely in contact. Specifically, the first microneedle forming hole 11 is a frustum structure, and the second microneedle forming hole 12 is a conical structure. The bottom of the second microneedle forming hole 12 is closed under normal pressure and forms a microneedle material channel under pressure. The inner diameter of the bottom of the frustum structure is the same as the inner diameter of the top of the conical structure, and the slopes of the frustum structure and the conical structure are the same. A tray 5 is provided at the bottom of the lower mold 4, and the tray 5 is detachably connected to the mold base 1.

[0040] To ensure that the microneedle material flows smoothly and evenly into the tray 5 through the first microneedle forming hole 11 and the second microneedle forming hole 12, this embodiment provides a cover plate 6 on the top of the upper mold 3. The cover plate 6 and the upper mold 3 are detachably and sealed together by a slot and a sealing ring structure. A pressure chamber 13 is formed between the cover plate 6 and the first microneedle forming hole 11. A through hole is provided at the center of the top of the cover plate 6. A high-pressure hose 7 is provided in the through hole. One end of the high-pressure hose 7 passes through the through hole and communicates with the pressure chamber 13. The other end of the high-pressure hose 7 is connected to an external micro air pump to introduce high-pressure gas into the pressure chamber 13 to pressurize the microneedle material poured into the upper mold 3, so that the microneedle material enters the tray 5 through the microneedle material channel at the bottom of the conical structure under pressure.

[0041] like Figure 3 and Figure 4 As shown, a volumetric groove 14, adapted to the number and position of the second microneedle forming holes 12, is provided inside the tray 5 to receive microneedle material from the microneedle material channel. To control the power and switching of the micropump based on the presence, absence, quantity, and amount of microneedle material in the volumetric groove 14, a sensor 15 is provided at the bottom of the volumetric groove 14. The microneedle mold also includes a controller, which is connected to both the sensor 15 and an external micropump. The controller acquires parameters from the sensor 15 and, based on built-in thresholds and control strategies, generates a power signal to control the micropump, thereby controlling the flow rate of the microneedle material. In this embodiment, a high-precision weighing sensor can be used to detect the microneedle material entering the volumetric groove 14.

[0042] To ensure a perfect fit between the upper mold 3 and the lower mold 4, in this embodiment, the lower mold 4 has a recessed structure. The bottom of the upper mold 3 is provided with a snap-fit ​​boss 10, and the outer edge of the snap-fit ​​boss 10 is provided with a sealing strip. When the upper mold 3 and the lower mold 4 are fitted together, the outer side of the sealing strip forms a sealing surface with the inner wall of the lower mold 4. To facilitate demolding, a release agent is applied to the inner walls of both the first microneedle forming hole 11 and the second microneedle forming hole 12.

[0043] It is important to emphasize that this application employs a split upper mold 3 and lower mold 4. To avoid microneedle material blockage and air bubble generation during casting, the upper mold 3 is made of rigid material, while the lower mold 4 is made of flexible material. To ensure that the second microneedle forming hole 12 is closed under normal pressure and forms a microneedle material channel under pressure, this application also provides a modified polydimethylsiloxane (PDMS) flexible material. The modified PDMS flexible material exhibits higher thermal stability and mechanical properties. The modified PDMS flexible material refers to a thiophene-modified PDMS flexible material (2-BMT / PDMS) obtained by treating a polydimethylsiloxane solution with ultraviolet ozone (UVO) to introduce hydroxyl groups onto the surface of the polydimethylsiloxane, followed by reaction with a 2-bromomethylthiophene solution. The specific preparation process is as follows:

[0044] A PDMS solution containing isooctyl acrylate solvent (the mixing ratio of isooctyl acrylate solvent and PDMS solution is 8-12%) was placed in a quartz glass bottle and stirred on a magnetic stirrer (stirring at 2500-3500 rpm for 25-35 min). The PDMS solution was then treated with UV light with optimized wavelength (UV ozone modification experiment used a UV ozone cleaner with a low-pressure mercury lamp as the light source, a power of 200-300W, and UV light wavelengths of 185nm and 254nm for 10-15 min). The UV ozone-treated PDMS solution was then placed in a brown glass bottle, and 2-bromomethylthiophene solution in different proportions (0-80% by mass) was added and stirred until the reaction was complete. Subsequently, a photoinitiator was added to the mixed solution, and after stirring evenly in the dark, it was allowed to stand. The mixture was then transferred to a mold and placed under a UV lamp for curing reaction to obtain thiophene-modified PDMS flexible material.

[0045] In this embodiment, the performance of PDMS flexible material is demonstrated through surface morphology characterization, thermal stability testing, and material mechanical property testing:

[0046] (1) Characterization of the surface morphology of PDMS flexible material:

[0047] The surface morphologies of untreated PDMS, 2-bromomethylthiophene (2-BMT) modified PDMS (20% 2-BMT / PDMS) without UVO treatment, UVO-treated PDMS (UVO / PDMS), and UVO-treated 2-BMT modified PDMS (20% 2-BMT / UVO / PDMS) were characterized using field emission scanning electron microscopy. Surface morphology images before and after UVO treatment and 2-BMT modification were also presented. Figure 5As shown, the surfaces of PDMS (A) without UVO treatment and 2-bromomethylthiophene (2-BMT) modified PDMS (20% 2-BMT / PDMS) (C) without UVO treatment are relatively smooth, resulting in poor mechanical properties. In contrast, PDMS (B) treated with UVO has a rough surface, and the 2-BMT modified PDMS (20% 2-BMT / UVO / PDMS) (D) after UVO treatment exhibits a small, granular structure. This is mainly because the thiophene-modified PDMS obtained through UVO wet treatment and nucleophilic substitution reaction with 2-BMT undergoes crosslinking under UV light, leading to the formation of chemical bonds and physical entanglement of molecular chains, resulting in a more ideal polymer structure.

[0048] (2) Thermal stability test of PDMS flexible material:

[0049] Medical materials typically require high-temperature sterilization before clinical use, thus necessitating good thermal stability. Different materials were subjected to thermal decomposition under nitrogen atmosphere at a heating rate of 10℃ / min, within a temperature range of 30℃-800℃. Table 1 shows the thermal stability results of UVO-treated modified PDMS flexible materials (2-BMT / UVO / PDMS) with different proportions of 2-bromomethylthiophene. As can be seen from Table 1, the initial decomposition temperature tends to increase with increasing 2-bromomethylthiophene content. The initial decomposition temperature T5 of the PDMS flexible material modified with 40% 2-bromomethylthiophene (40% 2-BMT / UVO / PDMS) reaches 497℃, which is 122℃ and 110℃ higher than the untreated or 2-bromomethylthiophene-modified PDMS control groups (PDMS and UVO / PDMS), respectively. Compared with the blank control group, the T10 of the 20% 2-BMT / UVO / PDMS loss 10% mass ratio increased by 24 and 32 °C, respectively. This demonstrates that UVO treatment and 2-bromomethylthiophene modification significantly enhance the thermal stability of PDMS flexible materials in the range of 30 °C to 500 °C.

[0050] Table 1. Thermogravimetric data of PDMS material

[0051]

[0052] (3) Mechanical property testing of PDMS flexible materials

[0053] Dumbbell-shaped mechanical property test samples of modified PDMS flexible materials (2-BMT / UVO / PDMS) with different 2-bromomethylthiophene addition amounts were prepared by UV curing using a mold. Uniaxial tensile tests were conducted using a universal testing machine under GB / T 528-2009 standard to investigate the effect of increasing 2-BMT content on the tensile mechanical properties of the modified PDMS flexible materials. Table 2 lists the tensile test data for 20% 2-BMT / PDMS and 40% 2-BMT / PDMS.

[0054] Table 22 - Mechanical property parameters of BMT / PDMS modified PDMS flexible materials

[0055] sample Tensile strength (MPa) Elongation at break (%) UVO / PDMS 0.17 41.14 20% 2-BMT / UVO / PDMS 2.22 72.29 40% 2-BMT / UVO / PDMS 6.49 60.81 60% 2-BMT / UVO / PDMS 7.81 50.10

[0056] Adding a higher mass ratio of 2-BMT to PDMS improves the mechanical properties of modified PDMS flexible materials, significantly enhancing both tensile strength and elongation at break. Table 2 shows that the maximum tensile strength of the 20% 2-BMT / UVO / PDMS composite is 2.22 MPa, and the maximum elongation at break is 72.29%. Adding 40% 2-BMT significantly increases the tensile strength of the modified material to 6.49 MPa, while reducing the elongation at break by 11.48%. This is because the thiophene-modified PDMS, obtained through UVO wet treatment and nucleophilic substitution with 2-BMT, exhibits enhanced tensile strength due to the formation of chemical bonds and physical entanglement of molecular chains during UV crosslinking. Furthermore, the increase in maximum elongation at break of 72.29% indicates a significant increase in the toughness of the modified PDMS flexible material.

[0057] Example 2

[0058] Based on the microneedle mold provided in Example 1, this example provides a microneedle forming method, including the following steps:

[0059] S1. Adjust the positions of the upper mold 3 and the lower mold 4, and use a positioning device to fix the position of the slider 9 so that the upper mold 3 and the lower mold 4 fit together tightly.

[0060] S2. Pour a certain amount of microneedle material into the upper part of the upper mold 3 and let it flow naturally.

[0061] S3. Install the cover plate 6 on the top of the upper mold 3 so that a pressure chamber 13 is formed inside the upper mold 3. Start the air pump to pressurize. Under the pressure, the material is pressed into the first micro-needle forming hole 11, the second micro-needle forming hole 12 and the inside of the tray in sequence.

[0062] S4. The controller monitors the data from sensor 15 in real time and forms a power signal to control the micro air pump based on the threshold and control strategy built into the controller, so as to control the flow rate of the micro needle material. When the micro needle material flows out in a columnar and uniform manner, the controller controls the micro air pump to stop pressurizing.

[0063] S5. Vacuum drying is performed while keeping the upper mold 3 and lower mold 4 in a fitted state.

[0064] S6. After drying, demold to obtain the microneedle array.

[0065] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A microneedle mold, characterized in that, It includes an upper mold (3) and a lower mold (4) disposed inside the mold fixing assembly, wherein the upper mold (3) is a rigid structure and the lower mold (4) is a flexible structure; The mold fixing assembly includes a mold base (1) and upright plates (2) disposed on both sides of the mold base (1). The upper mold (3) and the lower mold (4) are slidably connected to the upright plates (2) respectively. The upper mold (3) has a plurality of first microneedle forming holes (11) inside, and the lower mold (4) has a plurality of second microneedle forming holes (12) inside. The number and position of the first microneedle forming holes (11) and the second microneedle forming holes (12) are adapted to each other. The first microneedle forming hole (11) is a frustum structure, and the second microneedle forming hole (12) is a cone structure. The bottom of the second microneedle forming hole (12) is closed under normal pressure and forms a microneedle material channel under pressure. The bottom inner diameter of the frustum structure is the same as the top inner diameter of the cone structure, and the slopes of the frustum structure and the cone structure are the same. The bottom of the lower mold (4) is provided with a tray (5), and the tray (5) is detachably connected to the mold base (1).

2. The microneedle mold according to claim 1, characterized in that, The upper mold (3) is provided with a cover plate (6) on the top, and the cover plate (6) is detachably and sealingly connected to the upper mold (3); A pressure chamber (13) is formed between the cover plate (6) and the first microneedle forming hole (11). A through hole is provided at the center of the top of the cover plate (6). A high-pressure hose (7) is provided in the through hole. One end of the high-pressure hose (7) passes through the through hole and communicates with the pressure chamber (13). The other end of the high-pressure hose (7) is connected to an external micro air pump to introduce high-pressure gas into the pressure chamber (13) to pressurize the microneedle material poured into the upper mold (3), so that the microneedle material enters the tray (5) under pressure through the microneedle material channel at the bottom of the conical structure.

3. A microneedle mold according to claim 2, characterized in that, The tray (5) is provided with a volume groove (14) inside, which is adapted to the number and position of the second microneedle forming holes (12), for receiving microneedle material from the microneedle material channel; A sensor (15) is provided at the bottom of the volume groove (14), and the micro needle mold also includes a controller, which is connected to the sensor (15) and an external micro air pump respectively. The controller is used to acquire the parameters of the sensor (15) and form a power signal to control the micro air pump based on the threshold and control strategy built into the controller, so as to control the flow rate of the micro needle material.

4. A microneedle mold according to claim 3, characterized in that, Both sides of the upper mold (3) and the lower mold (4) are provided with sliders (9), and the sliders (9) are also provided with positioning devices for fixing the sliders (9). The inner side of the upright plate (2) is provided with a slide rail (8) adapted to the slider (9), and the slider (9) is slidably connected to the slide rail (8).

5. A microneedle mold according to claim 4, characterized in that, The lower mold (4) is a sunken structure. The bottom of the upper mold (3) is provided with a snap-fit ​​boss (10). The outer edge of the snap-fit ​​boss (10) is provided with a sealing strip. When the upper mold (3) and the lower mold (4) are in contact, the outer side of the sealing strip and the inner wall of the lower mold (4) form a sealing surface.

6. A microneedle mold according to claim 1, characterized in that, The inner walls of the first microneedle forming hole (11) and the second microneedle forming hole (12) are coated with a release agent.

7. A method for forming microneedles, characterized in that, The application of the microneedle mold according to claim 4 includes the following steps: Adjust the positions of the upper mold (3) and the lower mold (4), and use a positioning device to fix the position of the slider (9) so that the upper mold (3) and the lower mold (4) fit together tightly; A certain amount of microneedle material is poured into the upper part of the upper mold (3) and allowed to flow naturally; Install the cover plate (6) on the top of the upper mold (3) so that a pressure chamber (13) is formed inside the upper mold (3). Start the air pump to pressurize. Under the pressure, the material is pressed into the first micro-needle forming hole (11) and the second micro-needle forming hole (12) and the inside of the tray in sequence. The controller monitors the data of the sensor (15) in real time, and forms a power signal to control the micro air pump based on the threshold and control strategy built into the controller, so as to control the flow rate of the micro needle material. When the micro needle material flows out in a columnar and uniform manner, the controller controls the micro air pump to stop pressurizing. Vacuum drying is performed while keeping the upper mold (3) and lower mold (4) in a fitted state; After drying, the microneedle array is obtained by demolding.

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