Microneedle negative mold and preparation process and application thereof

Abstract

The application discloses a microneedle female die mold and a preparation process and application thereof, and belongs to the technical field of biomedical materials, and the preparation process comprises the following steps: step one, microprocessing is carried out on a silicon wafer by adopting MEMS technology, and a silicon-based microneedle is processed, and the silicon-based microneedle is used as a male die mold; step two, sputtering or evaporation is carried out on the silicon-based microneedle obtained in step one, so that a needle body part of the silicon-based microneedle is covered with a chromium seed layer as an adhesion layer, then electroplating or sputtering is carried out, so that the adhesion layer is covered with a chromium / nickel composite layer as a reinforcing layer, and a reinforced microneedle male die mold is obtained; step three, vacuum hot melting mold turning is carried out on the reinforced microneedle male die mold obtained in step two by using PMMA material, and a PMMA microneedle female die mold is obtained; and step four, the PMMA microneedle female die mold obtained in step three is treated by using plasma gas, the gas is one of air, oxygen and nitrogen, and a microneedle female die mold is obtained after treatment. The application has the advantages of reducing damage rate, prolonging service life, reducing cost and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biomedical materials, and relates to a microneedle mold, in particular to a microneedle female mold, a preparation process thereof and application. BACKGROUND

[0002] The microneedle is a micrometer-level needle array, which can be widely applied in the biomedical fields such as drug delivery, wound healing, biosensing and body fluid sampling as a new type of drug delivery system. The microneedle can non-invasively and painlessly penetrate the stratum corneum, produce systemic or local effect, and avoid some inconveniences caused by oral administration, such as liver first-pass effect, gastric acid hydrolysis, poor drug absorption and needle fear.

[0003] Since the microneedle preparation requires high precision, the microneedle mold is generally prepared by micro-electro-mechanical system (MEMS) technology. However, the cost of processing the microneedle mold by MEMS technology is high, and the silicon-based microneedle is prone to breakage during the mold turning process. In addition, the obtained polydimethylsiloxane (PDMS) female mold is prone to damage during long-term use, such as material aging, PDMS wear, yellowing, hardening, brittleness and performance deterioration. Therefore, the PDMS female mold needs to be continuously processed and prepared during the large-scale production of soluble microneedles, resulting in high production cost and low production efficiency. SUMMARY

[0004] In view of the technical problems of high depreciation rate of the PDMS female mold during the large-scale production of soluble microneedles, high production cost and low production efficiency, the present application provides a microneedle female mold, a preparation process thereof and application. The microneedle female mold has good stability and long service life, and can overcome the defects of the prior art.

[0005] To achieve the above-mentioned purpose, the present application provides a preparation process of a microneedle female mold, which has the following characteristics:

[0006] Step one, micro-processing is performed on a silicon wafer by MEMS technology to process a silicon-based microneedle, and the silicon-based microneedle is used as a male mold;

[0007] Step two, sputtering or evaporation is performed on the silicon-based microneedle obtained in step one to cover a chromium seed layer on the needle body of the silicon-based microneedle as an adhesion layer, and then electroplating or sputtering is performed to cover a chromium / nickel composite layer on the adhesion layer as a reinforcing layer, thereby obtaining a reinforced microneedle male mold. The adhesion layer can improve the adhesion of the silicon-based microneedle, thereby facilitating the adhesion of the reinforcing layer. The reinforcing layer is beneficial to protecting the relatively brittle silicon-based microneedle, so that the silicon-based microneedle is not prone to breakage during subsequent mold making and demolding, thereby obtaining a higher yield;

[0008] Step three, vacuum hot melting mold turning is performed on the reinforced microneedle male mold obtained in step two by using PMMA material to obtain a PMMA microneedle female mold;

[0009] Step four, treating the PMMA microneedle negative mold obtained in step three with a plasma gas, the gas being one of air, oxygen, and nitrogen, to obtain a microneedle negative mold mold after treatment; wherein the plasma treatment can improve the wettability of the PMMA microneedle negative mold, making it easier to spread liquid and demold in subsequent preparation of soluble microneedles.

[0010] Further, the present application provides a microneedle negative mold mold preparation process, which can also have the following features: in step one, the MEMS technology is ultraviolet lithography technology or X-ray radiation technology.

[0011] Further, the present application provides a microneedle negative mold mold preparation process, which can also have the following features: in step one, the specific method is: the silicon wafer is cleaned, dehydrated and baked, then the silicon wafer surface is spin-coated with photoresist using a high-speed spinner, and then the silicon wafer is exposed to ultraviolet or X-ray through a mask, and then baked at 115-130°C for 30-60s after exposure, and then baked at 120-150°C for 2-3min after development, and then checked for defects before proceeding to the next step.

[0012] Further, the present application provides a microneedle negative mold mold preparation process, which can also have the following features: in step two, the thickness of the adhesion layer is 50-300nm, preferably 100-150nm; the thickness of the reinforcing layer is 20-45μm, preferably 30μm.

[0013] Further, the present application provides a microneedle negative mold mold preparation process, which can also have the following features: in step three, the hot melt temperature of the vacuum hot melt mold turning is 160-250°C, preferably 210°C, and the vacuum degree is -0.08 to -0.1MPa, preferably -0.098MPa.

[0014] Further, the present application provides a microneedle negative mold mold preparation process, which can also have the following features: in step three, the specific method is: place the PMMA sheet above the reinforced microneedle positive mold obtained in step two, and then place the whole into a vacuum drying oven, heat to the hot melt temperature, remove bubbles by vacuumizing, maintain negative pressure for 1h, then take out the PMMA sheet and cool it; after cooling and solidification, remove the PMMA sheet from the reinforced microneedle positive mold, and then peel it off to obtain the PMMA microneedle negative mold.

[0015] Further, the present application provides a microneedle negative mold mold preparation process, which can also have the following features: in step four, the gas is oxygen.

[0016] Furthermore, the present invention provides a microneedle negative mold preparation process, which may also have the following characteristics: in step four, the plasma gas treatment time is 3 to 10 minutes.

[0017] The present invention also provides a microneedle negative mold prepared by the above-described preparation process.

[0018] The present invention also provides the application of the above-mentioned microneedle negative mold in the preparation of soluble microneedles.

[0019] The beneficial effects of this invention are as follows:

[0020] First, processing a chromium / nickel composite layer as a reinforcing layer can strengthen silicon-based microneedles, minimizing damage to the reinforced silicon-based male mold during the molding process and greatly improving the utilization rate of the male mold. Furthermore, a chromium seed layer is first sputtered or vapor-deposited as an adhesion layer between the reinforcing layers. This adhesion layer improves the adhesion of the silicon-based microneedles, facilitating the subsequent adhesion of the reinforcing layer.

[0021] Second, compared to PDMS microneedle negative molds, the PMMA microneedle negative molds obtained by the present invention have improved fabrication performance, are less prone to damage, are more durable, reduce the damage rate, and extend service life. This facilitates reuse in large-scale production of soluble microneedles, saving manufacturing costs and improving production efficiency, thus meeting the needs of scale-up production. Furthermore, the raw materials for PMMA microneedle negative molds are relatively inexpensive, further reducing manufacturing costs and meeting the demands of industrial production.

[0022] Third, plasma treatment is used to modify the hydrophilicity of the PMMA microneedle negative mold surface, thereby improving the wettability of the PMMA microneedle negative mold. This is beneficial for the subsequent preparation of soluble microneedles, such as making liquid spreading and demolding easier. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the preparation process of the microneedle negative mold of the present invention. Detailed Implementation

[0024] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0025] Example 1

[0026] like Figure 1 As shown, this embodiment provides a microneedle negative mold for preparing soluble microneedles. The preparation process of the microneedle negative mold includes the following steps:

[0027] Step one, using ultraviolet lithography technology directly on the silicon material micro-machining, prepared a silicon-based microneedle, with the silicon-based microneedle as a male mold, the specific method is: the silicon wafer is cleaned, dehydrated and baked, then the silicon wafer surface is spin-coated with photoresist by high-speed rotating machine, 100℃ soft baking for 45s to remove the solvent and harden, then the silicon wafer is exposed to ultraviolet light through the mask plate, after exposure, 120℃ baking for 50s, after development, 130℃ hard film baking for 2min, check no missing then proceed to the next step.

[0028] Step two, the silicon-based microneedle obtained in step one is put into a magnetron sputtering film coating machine to sputter a layer of chromium seed layer as an adhesion layer, and then sputter a layer of chromium / nickel composite layer as a reinforcing layer. The thickness of the adhesion layer is 100nm, and the thickness of the reinforcing layer is 30μm.

[0029] Step three, the reinforcing microneedle male mold with deposited reinforcing layer obtained in step two is poured with PMMA material, the specific method is: the PMMA sheet after mixing in an internal mixer is placed above the reinforcing microneedle male mold, and the whole is put into a vacuum drying oven, heated to 230℃, vacuumized to -0.098MPa to remove bubbles, maintained under negative pressure for 1h, then the PMMA sheet is taken out and cooled. After cooling and solidification, the PMMA material is removed from the reinforcing microneedle male mold to obtain a PMMA microneedle female mold.

[0030] Step four, the PMMA microneedle female mold obtained in step three is put into an oxygen plasma device for 5min of oxygen plasma treatment, and finally a microneedle female mold is obtained.

[0031] Example 2

[0032] As shown in Figure 1 , the present embodiment provides a microneedle female mold for preparing soluble microneedles, and the preparation process of the microneedle female mold comprises the following steps:

[0033] Step one, using x-ray radiation technology directly on the silicon material micro-machining, prepared a silicon-based microneedle, with the silicon-based microneedle as a male mold, the specific method is: the silicon wafer is cleaned, dehydrated and baked, then the silicon wafer surface is spin-coated with photoresist by high-speed rotating machine, 90℃ soft baking for 55s to remove the solvent and harden, then the silicon wafer is exposed to X-ray through the mask plate, after exposure, 115℃ baking for 60s, after development, 125℃ hard film baking for 150s, check no missing then proceed to the next step.

[0034] Step two, the silicon-based microneedle obtained in step one is put into a magnetron sputtering film coating machine to sputter a layer of chromium seed layer as an adhesion layer, and then sputter a layer of chromium / nickel composite layer as a reinforcing layer. The thickness of the adhesion layer is 150nm, and the thickness of the reinforcing layer is 30μm.

[0035] Step three, the PMMA material is poured on the reinforced microneedle positive mold obtained in step two, and the specific method is as follows: the well-mixed PMMA sheet is placed above the reinforced microneedle positive mold, the whole is placed in a vacuum drying oven, heated to 220°C, vacuumized to -0.098 MPa to remove bubbles, and maintained under negative pressure for 1 h, and then the PMMA sheet is taken out and cooled. After cooling and solidification, the PMMA material is removed from the reinforced microneedle positive mold, and a PMMA microneedle negative mold is obtained.

[0036] Step four, the PMMA microneedle negative mold obtained in step three is placed in a plasma treatment machine, and air plasma treatment is performed for 5 min, and finally a microneedle negative mold is obtained.

[0037] Example 3

[0038] As shown in the Figure 1 , the present embodiment provides a microneedle negative mold for preparing soluble microneedles, and the preparation process of the microneedle negative mold comprises the following steps:

[0039] Step one, a silicon-based microneedle is prepared by directly micro-machining on a silicon wafer material using ultraviolet lithography technology, and the specific method is as follows: the silicon wafer is cleaned, dehydrated and baked, then the silicon wafer surface is spin-coated with photoresist by a high-speed rotating machine, soft-baked at 110°C for 30 s to remove the solvent and harden it, then the silicon wafer is exposed to ultraviolet light through a mask, baked at 130°C for 30 s after exposure, and baked at 150°C for 2 min after development to make the film hard. If there is no defect, the next step is performed.

[0040] Step two, a chromium seed layer is evaporated on the silicon-based microneedle obtained in step one as an adhesion layer, and then a chromium / nickel composite layer is sputtered as a reinforcing layer. The thickness of the adhesion layer is 50 nm, and the thickness of the reinforcing layer is 20 μm.

[0041] Step three, the PMMA material is poured on the reinforced microneedle positive mold obtained in step two, and the specific method is as follows: the well-mixed PMMA sheet is placed above the reinforced microneedle positive mold, the whole is placed in a vacuum drying oven, heated to 210°C, vacuumized to -0.098 MPa to remove bubbles, and maintained under negative pressure for 1 h, and then the PMMA sheet is taken out and cooled. After cooling and solidification, the PMMA material is removed from the reinforced microneedle positive mold, and a PMMA microneedle negative mold is obtained.

[0042] Step four, the PMMA microneedle negative mold obtained in step three is placed in an oxygen plasma device, and oxygen plasma treatment is performed for 10 min, and finally a microneedle negative mold is obtained.

[0043] Example 4

[0044] As shown in the Figure 1As shown, the embodiment provides a microneedle negative mold for preparing soluble microneedles, and a preparation process of the microneedle negative mold comprises the following steps:

[0045] Step one, using x-ray radiation technology to directly microfabricate on the silicon wafer material, prepare a silicon-based microneedle, and the specific method is as follows: the silicon wafer is cleaned, dehydrated and baked, then the silicon wafer surface is spin-coated with photoresist by a high-speed rotating machine, soft-baked at 80°C for 60s to remove the solvent and harden, then the silicon wafer is exposed to x-rays through a mask plate, baked at 125°C for 40s after exposure, and baked at 150°C for 3min after development to make the film hard, and then the next step is performed if there is no defect.

[0046] Step two, the silicon-based microneedle obtained in step one is deposited with a chromium seed layer as an adhesion layer, and then a chromium / nickel composite layer is electroplated as a reinforcing layer. The thickness of the adhesion layer is 300nm, and the thickness of the reinforcing layer is 45μm.

[0047] Step three, the reinforcing microneedle positive mold with the reinforcing layer deposited in step two is poured with PMMA material, and the specific method is as follows: the well-mixed PMMA sheet is placed above the reinforcing microneedle positive mold, and the whole is placed in a vacuum drying oven, heated to 160°C, vacuumized to -0.08MPa to remove bubbles, and then the PMMA sheet is taken out after maintaining negative pressure for 1h and cooled. After cooling and solidification, the PMMA material is removed from the reinforcing microneedle positive mold to obtain a PMMA microneedle negative mold.

[0048] Step four, the PMMA microneedle negative mold obtained in step three is placed in a plasma treatment machine and treated with nitrogen plasma for 3min to obtain a microneedle negative mold.

[0049] In the present application, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. And the reagents, materials and operation steps used herein are widely used reagents, materials and conventional steps in the corresponding field.

[0050] Finally, it should be noted that: the above only describes the preferred embodiments of the present application and is not used to limit the present application, although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part of the technical features. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A process for preparing a microneedle negative mold, characterized in that: Includes the following steps: Step 1: Microfabrication is performed on a silicon wafer using MEMS technology to fabricate silicon-based microneedles, which are then used as positive molds. Step 2: Sputter or vapor deposit the silicon-based microneedles obtained in Step 1 to cover the needle body of the silicon-based microneedles with a chromium seed layer as an adhesion layer, and then electroplate or sputter to cover the adhesion layer with a chromium / nickel composite layer as a reinforcing layer to obtain a reinforced microneedle positive mold. Step 3: Place the PMMA sheet on top of the reinforced microneedle positive mold obtained in Step 2, and put the whole thing into a vacuum drying oven. Heat to the hot melt temperature of 160~250℃, evacuate to -0.08~-0.1MPa to remove air bubbles, maintain negative pressure for 1 hour, and then take out the PMMA sheet to cool. After cooling and curing, remove the PMMA sheet from the reinforced microneedle positive mold to obtain the PMMA microneedle negative mold. Step 4: Treat the PMMA microneedle female mold obtained in Step 3 with plasma gas, which is one of air, oxygen, or nitrogen. After treatment, the microneedle female mold is obtained.

2. The microneedle negative mold preparation process according to claim 1, characterized in that: in, In step one, the MEMS technology is ultraviolet lithography or X-ray radiation technology.

3. The microneedle negative mold preparation process according to claim 2, characterized in that: in, The specific method for step one is as follows: clean, dehydrate, and bake the silicon wafer. Then, spin-coat the surface of the silicon wafer with photoresist using a high-speed spin coater. Soft bake at 80~110℃ for 30~60s to remove the solvent and harden it. Then expose the silicon wafer to ultraviolet or X-rays through a mask. After exposure, bake at 115~130℃ for 30~60s. After development, hard bake at 120~150℃ for 2~3 minutes. If there are no defects, proceed to the next step.

4. The microneedle negative mold preparation process according to claim 3, characterized in that: in, In step two, the thickness of the adhesion layer is 50-300 nm; the thickness of the reinforcement layer is 20-45 μm.

5. The microneedle negative mold preparation process according to claim 1, characterized in that: in, In step four, the gas is oxygen.

6. The microneedle negative mold preparation process according to claim 1, characterized in that: in, In step four, the plasma gas treatment time is 3 to 10 minutes.

7. The microneedle negative mold prepared by the preparation process according to any one of claims 1 to 6.

8. The application of the microneedle negative mold as described in claim 7 in the preparation of soluble microneedles.

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