CN101862503B - Method for preparing off-plane hollow microneedle array for use in transdermal medicament administration - Google Patents

Abstract

The invention discloses a method for preparing an off-surface hollow microneedle array for transdermal drug delivery. A mask is grown on one side of a metal substrate to define a microneedle array pattern to form a mask pattern, and the other side is formed with a mask The perforated mark is aligned with the film pattern; then the perforated mark surface is protected, and the metal substrate is etched until the mask falls off to form an off-surface microneedle array; finally, the perforated mark surface is deprotected, and the perforated hole is aligned with the perforated mark. An out-of-plane hollow microneedle array is formed. The present invention realizes the preparation of out-of-plane hollow microneedle arrays based on micro-mechanical technology and positioning and punching technology. The needles can be fabricated at a higher height, thereby improving the reliability and insertion characteristics of the microneedle array.

Description

A preparation method of an off-plane hollow microneedle array for transdermal drug delivery

technical field

The invention relates to micromachining technology, in particular to a method for preparing a hollow microneedle array for transdermal administration.

Background technique

At present, the main modes of administration are oral and injection. Due to the gastrointestinal absorption and the first-pass effect of the liver, as well as the obvious pain caused by the injection and the need for professional operation, the microneedle transdermal drug delivery between subcutaneous injection and transdermal patch has become a better solution.

The size of the microneedles is on the order of microns, and through painless pore-forming treatment of the skin, tiny pores are created in the stratum corneum without blood vessels and nerves to improve the permeability of drugs. Due to the extremely small size of the needle tip, there is almost no damage to the skin, and it does not require professional training, so it is easy to use.

From the perspective of manufacturing process, microneedles are divided into two types: planar microneedles and off-surface microneedles. The needle axis of the former is parallel to the surface of the substrate, while the axis of the latter is perpendicular to the surface of the substrate. Obviously, off-surface microneedles are easier to form arrays and facilitate integration. From the perspective of internal structure, microneedles are divided into two types: solid microneedles and hollow microneedles. The former can create physical pores in the skin and transport drugs into the body in a permeable manner, while the latter can store drugs in the cavity. After the needle tip penetrates the skin, it is released into the body. It can be seen that hollow microneedles are more similar to traditional syringes, and transdermal drug delivery is more efficient. Therefore, the out-of-plane hollow microneedle array is an ideal microneedle structure.

In 1999, McAllister et al. used deep reactive ion etching (DRIE) to carve a hole along the center of each solid silicon microneedle to obtain an off-plane hollow silicon microneedle array (McMlister, DV, et al. Microneedles for transdermal delivery of macromolecules. BMES/EMBS Conf, 1999, 2: 836.). In the same year, Chun et al. used deep reactive ion etching, anisotropic etching, and silicon-glass bonding techniques to make hollow microneedles from the surface of silica (CHUN K, et al. An array of hollow microcapillaries for the controlled injection of genetic materials into animal/plantcells[A].Tech Dig 12 ^th IEEE Int Conf Micro Electro Mechanical Systems[C].Orlando, Florida, USA, 1999.406-411; CHUN K, et al.Fabrication of array of hollow micrecapillaries used for injection of genetic materials into animal/plant cels [J]. Jpn J Appl Phys 2, Lett, 1999, 38(3A): L279-L281.). In 2000, Steber et al. used deep reactive ion etching and isotropic etching technology to make silicon out-of-plane hollow microneedle arrays (STOEBER B, LIEPMANN D.Two-dimensional arrays of out-of-planeneedles[A].Proc. ASME Int.Mechanical Engineering Congr.and Exposition[C].Orlando, Florida, USA: ASME, 2000.355-359; STOEBER B, LIEPMANN D.Fluid injection throughout-of-plane microneedles[A].Proc 1st Annu Int IEEE.EMBS Spe.cial Topic Conf Microtechnologies Medicine and Biology [C]. Lyon, France, 2000.224-228.). In 2002, Griss et al. used three inductively coupled plasma (ICP) etching, combined with anisotropic and isotropic etching, to make microneedles with side openings (GRISS P, STEMME G.Side-opened out-of- plane microneedles for microfluidic transdermal liquid transfer [J]. Journal of Microelectromechanical Systems, 2003, 12(3): 296-288.). In 2003, Achim Trautmann and Mukejee et al. used anisotropic etching and isotropic etching techniques to fabricate hollow out-of-plane silicon microneedle arrays containing micropipes (TRAUTMANN A, TUTHER P, PAULO. Microneedle arrays fabricated using suspended etch mask technology combined with fluidic through wafer vias[A].Proc IEEE the 16th Annu Int Conf MEMS[C].Kyoto, Japan, 2003.682-685; MUKERJEE E V, et al.Microneedle array with integrated microchannels for transdermal sample extraction and IN SITU analysis is[A ].The 12th International Conference on Solid State Sensors, Actuators and Micronsystems[C].Boston, 2003.1439-1441; MUKERJEEE V, et al.Microneedle array for traudermal biological fluid extraction and in situanalysis[J]. , 114(2-3):267-275.). The above process requires a large number of deep etching processes of DRIE and ICP, which is costly and complicated. Due to the use of silicon-based materials, it is unavoidable that the silicon material itself is brittle and easy to break. At the same time, the silicon surface will also adsorb proteins, and the adhesion of white blood cells may cause stress reactions such as redness, swelling and inflammation. Therefore, silicon-based microneedles are not suitable for direct use in human treatment. Even if a biocompatible film is added in the subsequent process, it is difficult to fundamentally change this problem due to weak bonding reliability.

In 2003, Moon et al. used the inclined LIGA (German Lithographie, Galanoformung and Abformung three words, the abbreviation of lithography, electroforming and injection molding) technology to make off-plane hollow polymethyl methacrylate (PMMA) microneedles ( OKA K, et al. Fabrication of a microneedle for a trace blood test [J]. Sensors and Actuators A. 2002, 97-98: 478-485.). Ran Liu of Tsinghua University and others used UV-LIGA technology to make hollow SU-8 microneedles on a glass substrate (LIU R, et al. Microneedles array for fluid extraction and drug delivery [A]. 2003 International Symposium on Micromechatronics and Human Science [C]. New York, USA, 2003.239-244.). The hardness of polymer materials is not as good as silicon and metal microneedles, so it is difficult to effectively ensure insertion and effective depth. Moreover, new polymer materials are emerging one after another, and the material properties and processing technology are still to be matured, which requires further research and standardization work.

At present, the main metal hollow out-of-plane microneedles are mainly produced by LIGA and UV-LIGA electroforming processes. McAllister et al. used LIGA technology to make micromodels with solid silicon microneedles as tire molds, and then partially electroplated into hollow metal microneedles (McAllisterDV, et al.Three-dimensional hollow micmneedle and microtubearrays.Int, Conf, SS-Sens.Actuators, 10 ^th , Tokyo: 1EEE, I999, 1098-1010; DVMcAllister, et al, Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: Fabrication methods and transport studies.Proc, Nat.Acad.Sci., 2003, (100): .13755 -13760.). Davis et al. used improved LIGA technology (laser drilling, electroplating, corrosion) to process hollow nickel microneedle arrays of the same structure (Davis, SP, et al.Fabrication and characterization of lasermicromachined hollowmicroneedles.Trans, Sens, Actu & Micros, 12thInt , Conf, 2003, 2: 1435-1438; S.Davis, et al.Insertion of micronecdles into skin: measurement and prediction of insertion force and needle fracture force.J Biomechanics.2004, 1155-1163; Davis, et al.Hollow metalmicroneedles for insulin delivery to diabetic rats. Biomedical Engineering, IEEE Trans, 2005, 52: 909-915.). Kiyoshi Sawada et al. have made hollow microneedle arrays by plastic injection molding, which requires ultra-precision machining capabilities and high costs (Kiyoshi Sawada, et al.Micro structuring of high aspect ratio and array by means of mechanical machine.Int.Conf . Pre Engineering (ICPE), July 18-20, 2001.). LIGA and improved LIGA technology are more difficult to process, more expensive and relatively higher cost. At the same time, the bonding strength of the electroplated needle body and the substrate is not as reliable as the overall processing technology.

Contents of the invention

The purpose of the present invention is to provide a method for preparing an out-of-plane hollow microneedle array with simple process and low cost, and realize the preparation of the out-of-plane hollow microneedle array based on a micromechanical (MEMS) process and a positioning punching technology.

Technical scheme of the present invention is as follows:

A method for preparing an off-plane hollow microneedle array, comprising the steps of:

1) Growing a mask on one side of the metal substrate, defining the microneedle array pattern to form a mask pattern, and then aligning the mask pattern on the other side of the metal substrate to define a punching pattern to form a punching mark; or, first Define a punching pattern on one side of the metal substrate to form an opening mark, then grow a mask on the other side of the metal substrate, align the punching mark to define a microneedle array pattern, and form a mask pattern;

2) Protect the perforated marking surface of the metal substrate, etch the metal substrate until the mask falls off, forming an off-surface microneedle array;

3) Deprotect the surface of the punching mark, and punch holes in alignment with the punching mark to form an array of hollow microneedles away from the surface.

In the above step 1), the formation order of the punch marks and mask patterns can be adjusted, as long as the two are aligned with each other. The thickness of the metal substrate is preferably 50-2000 μm, and the material of the metal substrate is preferably titanium metal or titanium alloy; the mask material can be an organic polymer or an inorganic substance, and the organic polymer is such as parylene (Parylene) , the inorganic substances include metals (such as Ni) and semiconductor compounds (such as silicon dioxide, silicon nitride, etc.). The way to define microneedle array graphics can be photolithography, laser marking, screen printing, etc.; usually, etching is used to form mask graphics, and etching includes wet etching and dry etching, while spray etching belongs to wet etching. A type of corrosion. The method of defining the perforation pattern can also be photolithography, laser marking, silk screen printing, etc.; the method of forming the perforation mark can be wet etching or dry etching of the metal substrate.

For the formation of the mask pattern in step 1), the following method is preferably used: on one side of the metal substrate, physical vapor deposition methods such as sputtering and evaporation or chemical vapor deposition methods are used to generate a layer of mask, and the mask is coated with photoresist, and then photolithography defines the pattern of the microneedle array, and further etches away the exposed mask to form a mask pattern, and then removes the photoresist. When using a wet etching mask, the etching solution depends on the material of the substrate and the mask material. For example, for a titanium substrate and a nickel mask, a nickel-specific etching solution TFT can be used for wet etching. In order to increase the adhesion between the nickel mask and the titanium substrate, a thin layer of titanium can be sputtered on the surface of the substrate as an adhesion layer, and then a nickel mask can be formed on it.

For the formation of perforated marks in step 1), the following method is preferred: one side of the metal substrate is coated with photoresist, the photolithography defines the perforated pattern, then the exposed metal substrate is etched to form perforated marks, and then the photoresist is removed. Engraving.

In the above-mentioned step 2), the way to protect the perforated marking surface of the metal substrate can be to evenly coat protective glue (such as special protective glue or photoresist), or to grow a layer of organic polymers or inorganic substances (including metal and Inorganic semiconductor compound) mask, mechanical protection method (such as installing mechanical protection device) can also be used. The way of etching the metal substrate can be wet etching (including spray etching) or dry etching. The protective adhesive can be selected from ordinary positive photoresist such as Ruihong 304, or ProTEK adhesive, with a thickness of 1-2 μm, and of course it can be thicker.

In the above step 3), the way to protect the punching mark surface depends on the protection method, such as using a special glue remover, soaking with acetone, wet etching, dry etching, removing the mechanical protection device, etc.; The method can be laser drilling, ultrasonic drilling, electric spark drilling, etc. The punching marking surface is the entry surface for positioning the punching. According to the relative position of the hole and the microneedle, it can be divided into two types: the middle hole and the side hole.

The microneedle array prepared by the present invention is composed of a sheet-like substrate (i.e. a support) and a needle body array distributed thereon. The density of the microneedle array is determined by the microneedle array pattern defined in step 1), and the height of the microneedle is determined by the Depending on the thickness of the sheet and the degree of corrosion to the substrate, the morphology of the microneedles is mostly conical or polygonal.

The hollow microneedle array of the present invention can be widely used in transdermal drug delivery devices. The microneedles can pierce the skin stratum corneum to create physical holes to enhance drug delivery efficiency, especially for macromolecular drugs, which is a safe and painless transdermal drug delivery device. Method of administration. Because of the micro flow channel, the microneedle array of the present invention can be partially integrated with the injector and applied to painless micro injection and body fluid extraction with precise control. At the same time, the back of the support body is perforated to facilitate the integration of a liquid storage tank, and it can also be combined with a patch or implant to achieve the purpose of sustained drug release, thereby achieving more efficient, accurate, and long-term delivery of drugs.

The present invention realizes the preparation of out-of-plane hollow microneedle arrays based on micro-mechanical technology and positioning and punching technology, and adopts laser drilling and other positioning and punching technologies to drill holes, which can greatly increase the production of off-plane hollow microneedles compared with dry deep etching In particular, it makes it possible to process the metal substrate body of the hollow microneedle from the surface, thereby improving its reliability and insertion characteristics; moreover, the dry deep etching is difficult to realize for metals, and it is difficult to etch a large depth, and at the same time A series of lithography supporting processes are required, and the process is complicated. For different arrays, only the relevant CAD graphics files need to be replaced for positioning and punching, and there is no need to make and update masks, which simplifies the process flow.

Description of drawings

Figures 1a to 1k are process flow charts for preparing titanium-based out-of-plane hollow microneedles according to an embodiment of the present invention.

Fig. 2 is the microneedle morphology prepared by the wet etching step shown in Fig. 1i.

Fig. 3 is the morphology of the holes drilled by the laser on the titanium substrate.

Detailed ways:

Below in conjunction with the accompanying drawings, the present invention is further described in detail through the embodiments, but the scope of the present invention is not limited in any way.

Through mechanical processing of chemically pure titanium materials, four-inch titanium-based wafers are prepared by wire cutting. Low-temperature vacuum annealing and chemical-mechanical polishing were performed to obtain a 500 μm thick four-inch double-sided polished titanium-based wafer. Take a piece of the titanium substrate to prepare an off-plane hollow microneedle array according to the following steps:

1. Growth mask

The titanium substrate 1 was ultrasonically cleaned with acetone/alcohol for 10 minutes. After that, sputter a layer of 500nm thick nickel mask 2 successively on the polished surface of one side of the substrate (you can also sputter a layer of 20nm thick titanium on the surface of the substrate as an adhesion layer to increase the contact between the mask and the substrate. Adhesion), as shown in Figure 1a.

2. Form a mask pattern

On the nickel mask 2, a positive-type photoresist 3 is uniformly coated with a thickness of 1-2 μm, and a series of patterning processes such as pre-baking, exposure, development, and post-baking are performed to define a microneedle array pattern (as shown in Figure 1b ), where the exposure is 4s, and the film is hardened on a hot plate at 120°C for 60s, and developed until the graphics appear completely. Then use the special nickel etchant TFT to perform wet etching for 5-10 minutes until the exposed nickel layer is completely removed to form a microneedle mask pattern, as shown in Figure 1c. The photoresist 3 is subsequently removed, as shown in Figure 1d.

3. Form a punch mark

On the other side of the titanium substrate 1, evenly coat positive-type photoresist 4 (1-2 μm thick), align with the existing process surface (that is, the pattern surface of the nickel mask 2) and expose for 10 seconds, and harden the film on a hot plate at 130°C 30-60s, develop until the graphics completely appear, as shown in Figure 1e. Immerse in a solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) for 1 to 2 minutes to corrode the punch marks 5, as shown in Figure 1f. Then immerse in an acetone solution to remove the photoresist (see Figure 1g), and evenly apply ProTEK glue (protective glue 6) on the punched mark surface to prevent the punched mark 5 from being corroded by subsequent HF (see Figure 1h).

4. Laser alignment and drilling

A solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) is used for wet etching until the nickel mask 2 falls off and microneedles are formed, as shown in FIG. 1i. The average corrosion rate is 1 μm/min, and the specific time depends on the height of the corroded microneedles. Spray etching machines can also be used, and the etching time varies with machine parameters. The morphology of the microneedles prepared by wet etching in this step is shown in Figure 2, where A and B are images of microneedle morphology observed at different magnifications.

Use ProTEK Remover to remove the protective glue 6 (see Figure 1j), and use ultraviolet nanosecond laser fine micromachining equipment or picosecond green light laser fine micromachining equipment to punch holes from the punching mark surface to form a titanium-based out-of-plane hollow Microneedle array, as shown in Figure 1k. The morphology of laser drilling on titanium substrates is shown in Figure 3. The drilling diameters in A and B are 20.45 μm and 24.31 μm, respectively. The specific laser power varies from 3 to 50 W depending on the drilling depth, precision requirements, and equipment differences. The formed microneedles were immersed in a solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) for surface treatment to remove laser drilling residues, and finally formed titanium-based out-of-plane hollow microneedle arrays with better morphology.

Claims (6)

1. A method for preparing an off-plane hollow microneedle array, comprising the following steps: 1) growing a nickel mask on one side of the titanium substrate, defining a microneedle array pattern to form a mask pattern, and then aligning the mask pattern on the other side of the titanium substrate to define a punching pattern to form a punching mark; or, First define the punching pattern on one side of the titanium substrate to form a punching mark, then grow a nickel mask on the other side of the titanium substrate, align the punching mark to define a microneedle array pattern, and form a mask pattern; 2) Protect the punched marking surface of the titanium substrate, and use a solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) to etch the titanium substrate until the mask falls off, forming an off-surface microneedle array ; 3) Deprotect the punching mark surface, use ultraviolet nanosecond laser fine micromachining equipment or picosecond green light laser fine micromachining equipment, punch holes from the punching mark face to the punching mark, and form an off-surface hollow microneedle array . 2. The preparation method according to claim 1, characterized in that: the thickness of the titanium substrate is 50-2000 μm. 3. preparation method as claimed in claim 1, is characterized in that, adopts the method definition microneedle array pattern of photolithography, laser marking or screen printing in described step 1); Mask pattern is formed by etching by etching method; the perforation pattern is defined by photolithography, laser marking or screen printing; the perforation mark is formed by wet etching or dry etching on the titanium substrate. 4. The preparation method according to claim 1, characterized in that: step 1) after defining the pattern of the microneedle array, use TFT nickel etching solution to wet-etch the exposed mask part to form a mask pattern. 5. The preparation method according to claim 1, characterized in that: in said step 2), the way to protect the punched marking surface of the titanium substrate is to evenly coat ProTEK glue on the punched marking surface as the protective glue. 6. The preparation method as claimed in claim 1, characterized in that: step 3) cleaning the surface with a solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) after drilling.

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