Preparation method of an assembled hollow microneedle array

Abstract

The present invention discloses a preparation method of an assembled hollow microneedle array, which relates to the technical field of biomedical engineering and includes the following steps: Step 1, draw three-dimensional diagrams of the first assembly and the second assembly of the hollow microneedle array, obtain the male molds of the first assembly and the second assembly through 3D printing technology, and pour and cure the male molds of the first assembly and the second assembly to obtain the female molds of the first assembly and the second assembly; Step 2, respectively pour the polymer solution for preparing the microneedles into the female molds of the first assembly and the second assembly, take out the obtained first assembly and second assembly and dry them, and assemble the first assembly and the second assembly to obtain the hollow microneedle array. The present invention solves the problem that the through holes of the microneedles cannot be retained by means of reverse molding, and thus batch preparation can be realized, greatly reducing the problems of high cost and complex process existing in the current preparation of hollow microneedles.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical engineering, and particularly to a preparation method of an assembled hollow microneedle array based on a template method. Background Art

[0002] As an emerging transdermal delivery means, microneedles have advantages such as minimal pain and convenience, which can greatly reduce the resistance of patients during traditional injections. Compared with traditional sprays, ointments, etc., microneedles can greatly improve the drug delivery efficiency by destroying the stratum corneum structure and forming microchannels. However, due to the limitations of the volume of microneedles and the preparation process, it is difficult for microneedles to achieve large-dose and precise drug delivery. Hollow microneedles have advantages similar to traditional injection drug delivery. By inserting microneedles less than 1 mm into the subcutaneous tissue and using an injection device to achieve subcutaneous drug delivery, the problems of drug delivery amount and accuracy can be solved.

[0003] However, currently, the preparation of hollow microneedles mainly relies on methods such as photolithography, deep reactive ion etching, laser micromachining, integrated lithography technology, wet chemical etching, and micromachining. These methods have complex processes and expensive equipment, resulting in high preparation costs and difficulty in achieving batch production, and it is difficult to meet the needs of healthcare. Therefore, it is extremely important to find a preparation solution for hollow microneedles with low cost, high efficiency, high controllability, and batch production. Summary of the Invention

[0004] The purpose of the present invention is to provide a preparation method of an assembled hollow microneedle array, which solves the problems of complex processes, high costs, and low precision in the preparation of hollow microneedles in the prior art, and achieves the purpose of low cost, high efficiency, high controllability, and batch production.

[0005] To achieve the above purpose, the present invention provides the following solution:

[0006] The present invention provides a preparation method of an assembled hollow microneedle array, including the following steps:

[0007] Step 1, draw the three-dimensional diagrams of the first assembly and the second assembly of the hollow microneedle array, obtain the male molds of the first assembly and the second assembly through 3D printing technology, and pour and cure the male molds of the first assembly and the second assembly to obtain the female molds of the first assembly and the second assembly;

[0008] Step 2, respectively pour the polymer solution for preparing microneedles into the female molds of the first assembly and the second assembly, take out the obtained first assembly and second assembly and dry them, and assemble the first assembly and the second assembly to obtain the hollow microneedle array.

[0009] Preferably, in the first step, before casting and curing the male molds of the first assembly and the second assembly, the male molds of the first assembly and the second assembly are subjected to silanization treatment.

[0010] Preferably, in the first step, the silanized male molds of the first assembly and the second assembly are placed in a container, the PDMS mixture is mixed evenly and the bubbles are removed, the PDMS mixture is poured into the container to cover the male molds of the first assembly and the second assembly, then the container is placed in a vacuum drying oven, and then taken out and the container is heated and cured. After cooling, the female molds of the first assembly and the second assembly are taken out.

[0011] Preferably, in the second step, the polymer solution for preparing the microneedles is respectively poured into the female molds of the first assembly and the second assembly, so that the polymer solution completely fills the cavities of the female molds of the first assembly and the cavities of the female molds of the second assembly respectively. The residual organic solvents in the female molds of the first assembly and the second assembly are replaced. After the first assembly and the second assembly are respectively taken out from the female molds of the first assembly and the second assembly, after the first assembly and the second assembly are completely dried, the first assembly and the second assembly are assembled. After the assembly is completed, the joint between the first assembly and the second assembly is combined and sealed. The assembled hollow microneedle array is cleaned, disinfected and sterilized after drying, and then sealed and stored for subsequent use.

[0012] Preferably, the first assembly includes a first base, a groove is provided on the first base, a plurality of first microneedle assemblies and a plurality of first jacks are provided in the groove, the first jacks are located on one side of the first microneedle assemblies, and each of the first microneedle assemblies is provided with a first notch, and the first notch communicates with the first jack.

[0013] Preferably, the second assembly includes a second base, a plurality of second microneedle assemblies and a plurality of second jacks are provided on the second base, the second microneedle assemblies match the first jacks, the second jacks match the first microneedle assemblies, the second jacks are located on one side of the second microneedle assemblies, and each of the second microneedle assemblies is provided with a second notch, and the second notch communicates with the second jack. After the first assembly and the second assembly are assembled, the first microneedle assemblies and the second microneedle assemblies form microneedles, and the first notches and the second notches form through holes.

[0014] Preferably, the through hole and the microneedle are not coaxial, and the axis of the through hole is arranged parallel to the axis of the microneedle.

[0015] Preferably, the shape of the second base matches the shape of the groove.

[0016] Preferably, there is at least one of the first assembly and the second assembly.

[0017] The present invention has achieved the following technical effects compared with the prior art:

[0018] The present invention discloses a method for low-cost and batch preparation of hollow microneedle arrays. By dividing the microneedles into two parts and using an up-and-down assembly method, the hollow microneedles are prepared by the reverse molding method. By dividing the microneedles into two parts, the present invention solves the problem that the through holes of the microneedles cannot be retained by the reverse molding means, and thus batch preparation can be achieved, greatly reducing the problems of high cost and complex process existing in the current preparation of hollow microneedles. In subsequent applications, it can be combined with an injection device to achieve painless, precise, and large-dose transdermal drug delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0020] Figure 1 Schematic diagram of the preparation method of the assembled hollow microneedle array of the present invention;

[0021] Figure 2 Axonometric view of the first combination of the present invention;

[0022] Figure 3 Top view of the first combination of the present invention;

[0023] Figure 4 For Figure 3 Local enlarged view at I;

[0024] Figure 5 Side view of the first combination of the present invention;

[0025] Figure 6 Axonometric view of the second combination of the present invention;

[0026] Figure 7 Top view of the second combination of the present invention;

[0027] Figure 8 For Figure 7 Local enlarged view at II;

[0028] Figure 9 Side view of the second combination of the present invention;

[0029] Figure 10Isometric view of the hollow microneedle array of the present invention;

[0030] Figure 11 Top view of the hollow microneedle array of the present invention;

[0031] Figure 12 Is Figure 11 Local enlarged view of part Ⅲ of

[0032] Wherein: 1 - first base, 2 - groove, 3 - first microneedle assembly, 4 - first jack, 5 - first notch, 6 - second base, 7 - second microneedle assembly, 8 - second jack, 9 - second notch, 10 - through hole. Specific implementation manner

[0033] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0034] The purpose of the present invention is to provide a preparation method for an assembled hollow microneedle array, which solves the problems of complex process, high cost, low accuracy, etc. in the preparation of hollow microneedles in the prior art, and realizes the purpose of low-cost, high-efficiency, highly controllable and batch production.

[0035] In order to make the above objects, features and advantages of the present invention more obvious and understandable, the present invention will be further described in detail below in conjunction with the accompanying drawings and specific implementation manners.

[0036] As Figure 1 shown: This embodiment provides a preparation method for an assembled hollow microneedle array, including the following steps:

[0037] Step 1: Use Solidworks software to draw the 3D models of the first and second assemblies of the hollow microneedle array. Obtain the male molds of the first and second assemblies through 3D printing technology. The advantage of 3D printing technology is high controllability and precise structure. Pour and cure the male molds of the first and second assemblies. Use silanization treatment such as OTS (octadecyltrichlorosilane) and TMCS (trimethylchlorosilane) on the male molds of the first and second assemblies, which is beneficial for the subsequent demolding of the female molds of the first and second assemblies. Place the silanized male molds of the first and second assemblies in a container. The prepared PDMS mixture includes polydimethylsiloxane and a curing agent. The curing agent is Dow Corning Sylgard 184, and the ratio of polydimethylsiloxane to the curing agent is 10:1. Mix the PDMS mixture evenly and remove the bubbles. Pour the PDMS mixture into the container to cover the male molds of the first and second assemblies. Then place the container in a vacuum drying oven, and then take it out and heat-cure the container. After cooling, take out the female molds of the first and second assemblies to obtain the female molds of the first and second assemblies;

[0038] Step 2: Pour the polymer solutions for preparing the microneedles into the female molds of the first and second assemblies respectively. Use centrifugation, bottom vacuum method, and molding method to make the polymer solutions completely fill the cavities of the female molds of the first and second assemblies respectively. Replace the residual organic solvents in the female molds of the first and second assemblies. After taking out the first and second assemblies from the female molds of the first and second assemblies respectively, wait until the first and second assemblies are completely dry, then assemble the first and second assemblies up and down. After the assembly is completed, use methods such as heat sealing and surface gold plating to seal the connection between the first and second assemblies. Clean the assembled hollow microneedle array, disinfect and sterilize it after drying, and store it sealed for subsequent use.

[0039] In this embodiment, the matrix of the polymer solution is one or more of polylactic acid, polycaprolactone, cross-linked hyaluronic acid, cross-linked gelatin, polyethylene, polypropylene, polytetrafluoroethylene, phenolic resin, ABS resin, polystyrene, polyester, polycarbonate, and polymethyl methacrylate; the solvent of the polymer solution is one or more of water, alcohol, chloroform, dichloromethane, trichloromethane, methanol, pain, xylene, dioxane, tetrahydrofuran, and N-methylpyrrolidone.

[0040] In this embodiment, as Figures 2 - 5As shown, there is at least one first assembly and at least one second assembly. The first assembly includes a first base 1, on which there is a groove 2. In the groove 2, there are several first microneedle assemblies 3 and several first jacks 4. The first jacks 4 are located on one side of the first microneedle assemblies 3. Each first microneedle assembly 3 is provided with a first notch 5, and the first notch 5 communicates with the first jack 4.

[0041] In this embodiment, as Figures 6 - 12 shown, the second assembly includes a second base 6. The shape of the second base 6 matches the shape of the groove 2. On the second base 6, there are several second microneedle assemblies 7 and several second jacks 8. The second microneedle assemblies 7 match the first jacks 4, and the second jacks 8 match the first microneedle assemblies 3. The second jacks 8 are located on one side of the second microneedle assemblies 7. Each second microneedle assembly 7 is provided with a second notch 9, and the second notch 9 communicates with the second jack 8. After the first assembly and the second assembly are assembled, the first microneedle assemblies 3 and the second microneedle assemblies 7 form microneedles, and the first notch 5 and the second notch 9 form a through hole 10. The through hole 10 is not coaxial with the microneedle, and the axis of the through hole 10 is arranged parallel to the axis of the microneedle. The microneedle adopts a side-opening scheme to avoid blockage when piercing the skin. The distance between the axis of the through hole 10 and the axis of the microneedle is 10 - 400 μm, and the size of the through hole 10 is 20 - 200 μm.

[0042] In this embodiment, the shape of the first base 1 includes but is not limited to: square, circle, ellipse, rectangle, triangle, rhombus, etc.; the shape of the second base 6 includes but is not limited to: square, circle, ellipse, rectangle, triangle, rhombus, etc.

[0043] In this embodiment, the hollow microneedle array includes but is not limited to: square 3*3, 4*4, 5*5*, 10*10, etc., rectangle 2*5, 3*8, etc., triangle, circle. The height of the microneedle is 50 - 2000 μm, the bottom diameter of the microneedle is 25 - 1200 μm, and the distance between adjacent microneedles is 50 - 1500 μm.

[0044] In this embodiment, by dividing the hollow microneedle into two parts, it is possible to avoid the problem that the hollow structure in the female mold is easily broken and difficult to retain and maintain the template for repeated use during the preparation of the polymer female mold. Compared with other preparation methods of hollow microneedles, such as photolithography, deep reactive ion etching, laser micromachining, integrated lithography, wet chemical etching and micromachining, etc., the template method adopted in this embodiment has the advantages of repeatability and batch preparation, and can greatly reduce the preparation cost of hollow microneedles. The assembly method can improve the preparation success rate of the polymer template, ensure the efficient use of the template, and then combined with a syringe, it provides a high-dose and high-precision drug delivery scheme for transdermal drug delivery of microneedles.

[0045] Application Example

[0046] Step 1: Use Solidworks to draw the 3D models of the first assembly and the second assembly. The microneedles are conical, with a microneedle height of 1.2 mm, a spacing of 1 mm, a base diameter of 0.8 mm, the size of the through hole 10 is 80 μm, and the distance from the axis of the through hole 10 to the axis of the microneedle is 0.1 mm. Then, print the male molds of the first assembly and the second assembly through a 3D printer. Before casting the mold, silanize the surfaces of the male molds of the first assembly and the second assembly with trimethylchlorosilane;

[0047] Place the silanized male molds of the first assembly and the second assembly in a glass dish. Mix polydimethylsiloxane and a curing agent in a ratio of 10:1 evenly and put them into a vacuum drying oven to remove air bubbles. Pour the PDMS mixture into the glass dish to cover the male molds of the first assembly and the second assembly. Then, place the glass dish in the vacuum drying oven for 1 hour. Subsequently, take it out and place the glass dish in an oven at 60 °C to heat and cure for 2 hours. After cooling, take out the 3D printed assembly parts to obtain the female molds of the first assembly and the second assembly;

[0048] After ultrasonic cleaning and drying, encapsulate and preserve the female molds of the first assembly and the second assembly after the above-mentioned mold casting is completed, and mark the microneedle size parameters;

[0049] Step 2: Prepare a polymer solution. Taking polylactic acid as an example, use dioxane as the solvent. Weigh 2 g of polylactic acid and add 10 mL of dioxane, and heat it to 90 °C to prepare a 20% polymer solution. Fill the polymer solution into the female molds of the first assembly and the second assembly. Apply negative pressure through a vacuum device on the back of the female molds of the first assembly and the second assembly to completely fill the cavities of the female molds of the first assembly and the second assembly with the polymer solution. After 0.5 hours, immerse the female molds of the first assembly and the second assembly in ultrapure water to displace the remaining organic solvents, or fill the polymer solution into the female molds of the first assembly and the second assembly by centrifugation;

[0050] After taking out the first assembly and the second assembly from the female molds of the first assembly and the second assembly respectively, place them in a vacuum drying oven to dry for 6 hours. After they are completely dry, assemble the first assembly and the second assembly up and down. After the assembly is completed, place it in an oven at 90 °C to heat for 10 min to seal the joint of the separated first assembly and the second assembly. Ultrasonically clean the prepared assembled hollow microneedle array, dry it, disinfect and sterilize it, and then seal and preserve it for subsequent use.

[0051] In this specification, specific examples are used to elaborate on the principles and implementation modes of the present invention. The description of the above embodiments is only for helping to understand the method and its core idea of the present invention; meanwhile, for those of ordinary skill in the art, according to the idea of the present invention, there will be changes in the specific implementation modes and application scopes. In summary, the content of this specification should not be construed as a limitation on the present invention.

Claims

1. A preparation method of an assembled hollow microneedle array, characterized in that: It includes the following steps: Step 1: Draw the 3D diagrams of the first and second assemblies of the hollow microneedle array. Obtain the male molds of the first and second assemblies through 3D printing technology. Pour and cure the male molds of the first and second assemblies to obtain the female molds of the first and second assemblies. Step 2: Respectively pour the polymer solution for preparing microneedles into the female molds of the first and second assemblies. After taking out the obtained first and second assemblies and drying them, assemble the first and second assemblies to obtain a hollow microneedle array. The first assembly includes a first base, on which there are grooves. In the grooves, there are several first microneedle components and several first jacks. The first jacks are located on one side of the first microneedle components. Each of the first microneedle components is provided with a first notch, and the first notch communicates with the first jack. The second assembly includes a second base, on which there are several second microneedle components and several second jacks. The second microneedle components match the first jacks, and the second jacks match the first microneedle components. The second jacks are located on one side of the second microneedle components. Each of the second microneedle components is provided with a second notch, and the second notch communicates with the second jack. After the first and second assemblies are assembled, the first and second microneedle components form microneedles, and the first and second notches form through holes.

2. The preparation method of the assembled hollow microneedle array according to claim 1, characterized in that: In Step 1, before pouring and curing the male molds of the first and second assemblies, perform silanization treatment on the male molds of the first and second assemblies.

3. The preparation method of the assembled hollow microneedle array according to claim 2, wherein: In Step 1, place the silanized male molds of the first and second assemblies in a container. Mix the PDMS mixture evenly and remove the bubbles. Pour the PDMS mixture into the container to submerge the male molds of the first and second assemblies. Then place the container in a vacuum drying oven, and then take it out. Heat and cure the container. After cooling, take out the female molds of the first and second assemblies.

4. The preparation method of the assembled hollow microneedle array according to claim 1, characterized in that: In Step 2, respectively pour the polymer solution for preparing microneedles into the female molds of the first and second assemblies so that the polymer solution completely fills the cavities of the female molds of the first and second assemblies respectively. Replace the residual organic solvents in the female molds of the first and second assemblies. After taking out the first and second assemblies from the female molds of the first and second assemblies respectively, after the first and second assemblies are completely dried, assemble the first and second assemblies. After the assembly is completed, seal the joint of the first and second assemblies. Clean the assembled hollow microneedle array, disinfect and sterilize it after drying, and then seal and store it for subsequent use.

5. The preparation method of the assembled hollow microneedle array according to claim 1, characterized in that: The through hole is not coaxial with the microneedle, and the axis of the through hole is parallel to the axis of the microneedle.

6. The preparation method of the assembled hollow microneedle array according to claim 1, characterized in that: The shape of the second base matches the shape of the groove.

7. The preparation method of the assembled hollow microneedle array according to claim 1, wherein: Both the first assembly and the second assembly are at least one.

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