CN101905856B - Method for preparing plane hollow microneedle for transdermal administration - Google Patents

Abstract

The invention discloses a method for preparing a planar hollow microneedle for transdermal drug delivery. A microneedle flow channel pattern is defined on one side of a first metal substrate to form a channel, and a microneedle pattern is defined on the other side to form a cut Marking, wherein the flow channel pattern is aligned with the central axis of the microneedle pattern; the second metal substrate is bonded to the channel surface of the first metal substrate; the non-bonded surface of the second metal substrate is thinned, And align the cutting marks on the first metal substrate to the non-bonding surface of the second metal substrate; thin the non-bonding surface of the first metal substrate, and then align the cutting marks on the second metal substrate Cut to form planar hollow microneedles. The method is based on the micro-machining technology and combines the traditional machining and cutting technology, which reduces the difficulty of the process and enhances the reliability of the micro-needle, which is beneficial to mass production.

Description

A preparation method of planar hollow microneedles for transdermal drug delivery

technical field

The invention relates to micromachining technology, in particular to a method for preparing a planar hollow microneedle for transdermal drug delivery. the

Background technique

At present, the main modes of administration are oral and injection. Due to the absorption in the stomach and the first-pass effect of the liver, the actual efficacy of the drug on the site of action is greatly affected by the oral drug. Injection will not only bring obvious pain to patients, but also requires professional operation, and may even cause local skin damage or even infection, which is not suitable for long-term and precise controlled sustained-release drug delivery. the

Transdermal administration is a better solution. The skin is divided into three layers from outside to inside: stratum corneum, epidermis and dermis. The stratum corneum is about 10-20 microns thick and is a layer of dead tissue without blood vessels and nerves; the epidermis is located about 50-100 microns below the epidermis and contains a small amount of living cells and nerves without blood vessels; the deeper dermis also contains A large number of living cells, nerves and blood vessels. It can be seen that the stratum corneum is the biggest barrier for drug transdermal absorption. For this reason, various physical and chemical methods have been adopted to promote the percutaneous absorption of drugs. Physical methods such as iontophoresis, ultrasound, electroporation, and thermal perforation have remarkable percutaneous absorption effects, but most of them need to rely on electronically controlled equipment with energy sources, which cause great damage to the skin, and users cannot use them independently . However, chemical penetration enhancers have no obvious effect on the percutaneous absorption of macromolecular drugs, and generally have strong irritation. the

In comparison, microneedle transdermal drug delivery is a drug delivery method between subcutaneous injection and transdermal patch. Microneedle also belongs to the physical penetration enhancement technology. It is a needle-like structure with a size in the micron range made of different shapes and materials made by micro-fabrication technology. Micro-pores improve the permeability of drugs, thereby greatly increasing the transdermal absorption of drugs, especially macromolecular drugs; at the same time, due to the extremely small size of the needle tip, there is almost no damage to the skin, and it is easy to use, does not require professional training, and is suitable for individual independent operation . the

According to the materials used to make them, there are three main types of microneedles: silicon, polymers, and metals. Silicon material has a mature micro-processing technology and is easy to mass produce, but its biocompatibility is poor, and it is easy to break and stay in the skin, which is a key factor restricting its development. Polymer microneedles have good biocompatibility and are degradable, but their strength is poor, and the discovery of new materials and processing technology need to be improved. Metal microneedles are cheap and simple in process, suitable for mass production, and have sharp needle tips and high hardness, which are easy to pierce the skin and not easy to break. Metals such as biocompatible titanium, nickel, and stainless steel are good materials for making microneedles. the

According to the manufacturing process, there are mainly two types of microneedles: off-plane and flat. The axis of the former is perpendicular to the surface of the substrate, while the axis of the latter is parallel to the surface of the substrate. The off-surface microneedle, especially for the off-surface microneedle with a large aspect ratio, is complex and difficult to control, difficult and expensive. The planar microneedle is relatively simple in process, the shape of the microneedle is convenient to control, and it is easy to combine with other processes to integrate microchannels, sensors, etc. to form a microinjection control system. the

According to the internal structure, there are mainly two types of microneedles: solid and hollow. The former can create physical holes in the skin and transport the drug into the body in a permeable manner; the latter can store the drug in the cavity and wait for the needle tip to penetrate released into the body after the skin. It can be seen that hollow microneedles are more similar to traditional syringes, and transdermal drug delivery is more efficient. the

In 1997, Chen et al. used the anisotropic self-stop corrosion technology of silicon to make a silicon-based planar hollow microneedle with microchannels (CHEN J, et al. A multichannel neural probe for selective chemical Delivery at the Cellular Level[J ]. IEEE Transactions on Biomedical Engineering, 1997, 44(8): 760-769.). In 1999, Lin et al. made silicon nitride microneedles using similar technology (LIN L, PISANO A P. Silicon-Processed Microneedles [J]. IEEE Journal of Microelectmmechanical Systems, 1999, 8 (1): 78-84.). In 2002, Oka et al used corrosive fluid drilling to form silicon serrations, combined with silicon-silicon bonding, plasma etching and confocal ion beam bombardment etching technology to make planar hollow silicon microneedles (OKAK, et al .Fabrication of a microneedle for a trace blood test[J].Sensors and Actuators A, 2002, 97-98: 478-485). In 2004, Paik et al. used dry etching and channel refilling technology to make a single crystal silicon planar hollow microneedle array (PAIK S J, et al. A novel microneedle array integrated with a PDMS biochip for microfluid systems[A] .The 12th International Conference on Solid State Sensors, Actuators and Microsystems[C].Boston: 2003.146-1449; PAIK S J, et al.In-plane single-crystal-silicon microneedles for minimally invasive microfluid systerns[J].Sensors and Actuators A: Physical, 2004, 114(2-3): 276-284). Due to the use of silicon-based materials, most of the mature silicon processing technology can be used, but at the same time, the problems of silicon materials themselves cannot be avoided. In addition to the fact that silicon microneedles are brittle and easy to break, the surface of silicon also adsorbs proteins, causing white blood cells to adhere to the surface of the microneedles, which may cause stress reactions such as redness, swelling, and inflammation. Therefore, silicon microneedles are not suitable for direct use in human treatment. Even if a gold film is added in the follow-up process, it is difficult to fundamentally change this problem due to the weak combination reliability of the surface film process. the

At the end of the last century, Frazier and others used surface micromachining technology combined with low temperature conditions to process coplanar hollow palladium microneedles (Paputsky, et al. A low temperature IC compatible process for fabricating surfacemicromachined metallic microchannels.IEEE J Microelectromech Sys, 1998, 7(2): 267-273; J.Brazzle, et al.Fluid-coupled metallic micromachined needle arrays.20thinter.ConeIEEE.Med&Bio Society, Hong Kong, 1998.1837-1840; J.Brazzle, et al.Hollow metallic micromachined needle arrays.J.Micro Biom Devices, 2000, 2: 197-205.). Its colleague Chandrasekaran etc. have also processed similar microneedles (S.Chandrasekaran, et al.Surface micromachined metallic microneedles, J Microelectromech Sys, 2003, (12): 281-288.). The above-mentioned microneedle preparation process is designed for low-temperature processing, which is difficult and costly, and the structural characteristics and quality control are not easy to guarantee. In 2006, Parker et al. used deep etching and gold-gold bonding to produce titanium-based microneedles (E.R. Parker, et al.Bulk Titanium Microneedles with Embedded Microfluidic Networks for Transdermal Drug Delivery. IEEEMEMS 2006, Istanbul, Turkey, 22-26January 2006: 498-501.). This has greatly improved and improved in terms of material and processing technology. However, due to the weak bonding strength of the gold-gold bond, the safety and reliability of the microneedle as an insertion device has yet to be tested. At the same time, the deep etching process that uses too much titanium has high requirements on the process itself, is difficult, and the cost is correspondingly increased. In addition, the small chip processing technology it adopts does not match the traditional silicon wafer processing technology and is not suitable for mass production. In 2009, Yan Xiaoxiao of Shanghai Jiaotong University and others used electroplating technology to prepare a 50 μm thick nickel plane microneedle, and then deposited a 2 micron polymer growth biocompatibility (YAN Xiao-xiao, et al.MEMS In-Plane Metallic Microneedle for Drug Delivery. Nanotechnology and Precision Engineering, Sep.2009, Vol.7No.5: 419-422). The microneedles prepared by electroplating have a weak bonding force with the substrate, and the deposited polymer is also easy to fall off, so the overall reliability and ease of use need to be improved. the

Contents of the invention

The purpose of the present invention is to provide a method for preparing a planar hollow microneedle for transdermal drug delivery. The method is based on micromachining technology and combines traditional machining and cutting techniques to enhance the reliability of the microneedle and reduce the Technological difficulty, and achieve mass production. the

Technical scheme of the present invention is as follows:

A preparation method of planar hollow microneedles, comprising the following steps:

1) Define the microneedle flow pattern on one side of the first metal substrate to form a channel, and then define the microneedle pattern on the other side to align with the channel position to form a cutting mark; or, first on the first metal substrate Define the microneedle pattern on one side to form a cutting mark, and then align the microneedle pattern on the other side to define the microneedle flow channel pattern to form a channel;

2) Take a second metal substrate and bond it to the channel surface of the first metal substrate;

3) thinning the non-bonding surface of the second metal substrate, and aligning and transferring the cutting marks on the first metal substrate to the non-bonding surface of the second metal substrate;

4) Thinning the non-bonding surface of the first metal substrate, and then cutting in alignment with the cutting marks on the second metal substrate to form a planar hollow microneedle. the

The formation sequence of channels and cutting marks in the above step 1) can be adjusted, as long as the microneedle pattern and the flow channel pattern are aligned with each other, generally the flow path pattern is aligned with the central axis of the microneedle pattern. The way to define graphics can be photolithography, laser marking, screen printing, etc. The way to form trenches and cutting marks can be to perform wet etching or dry etching on the substrate, and the way of wet etching includes Soak in corrosive liquid corrosion and spray corrosion. the

For step 1), the following method is preferably used to form the channel: one side of the first metal substrate is coated with photoresist, and the photolithography defines the internal channel pattern of the microneedle, and then the first metal is etched with the photoresist as a mask. The substrate forms the channel. The photoresist used is used as a mask in the etching process, preferably a negative photoresist resistant to etching such as SU8; the formation of the channel generally adopts dry etching, such as using reactive ion etching (RIE) technology, etching The etch depth depends on the dimension design of the channel and the microneedle. the

For step 1) the following method is preferably formed in the formation of cutting marks: the other side of the first metal substrate is coated with photoresist, and photolithography defines the exposed part of the first metal substrate after wet etching to form cutting marks , and then remove the photoresist. The photoresist used may be a positive photoresist; the cutting mark is formed by wet etching, and the etching solution used depends on the material of the substrate. The etching time is very short, generally 1-2min, so even if the channel is formed first, the corrosion process has little effect on the channel. To protect the channel, the channel can also be protected (such as coated with protective glue) after the channel is formed, and then the cutting marks can be formed. the

The material of the above step 2) the second metal substrate is generally the same as that of the first metal substrate, and optional metal materials include but not limited to titanium, stainless steel, nickel or their alloys, preferably titanium. All the metal substrates of the present invention are generally selected as flat sheets, and the thickness is generally 50-2000 μm. Most preferably, both the first metal substrate and the second metal substrate use a 4-inch titanium-based wafer. The first metal substrate is double-sided polished, the second metal substrate can be single-sided or double-sided polished, the bonding surface of the second metal substrate and the first metal substrate is a polished surface, and the bonding method can be adopted The surface is directly bonded (such as diffusion welding bonding), and the middle layer bonding can also be used. Diffusion bonding is usually performed in a vacuum environment of 1×10 ^-4 Pa, at a temperature of about 1000-1200°C, and kept under pressure for 1-2 hours, wherein the relationship between pressure and time is inversely proportional.

The method of transferring the pattern of the cutting mark in the above step 3) may be alignment photolithography, laser marking, screen printing, etc., and then wet etching or dry etching the second metal substrate to obtain the cutting mark on its non-bonding surface. Preferably, photoresist is coated after thinning and polishing the non-bonding surface of the second metal substrate, and photolithography is carried out in alignment with the cutting marks on the first metal substrate, and then the cutting marks are etched on the second metal substrate by wet etching. Transfer from the first metal substrate to the second metal substrate, and then remove the photoresist. The photoresist used is generally a positive photoresist, and the wet etching transfers the cutting mark, and the etching solution used depends on the material of the metal substrate. the

In the above step 3) and step 4), methods such as wet etching (including spray etching) or chemical mechanical polishing can be used to thin the metal substrate. The thickness of the final formed planar microneedles depends on the bonding sheet thickness and thinning thickness. the

The cutting method in the above step 4) can be laser cutting, wire cutting, ion beam cutting, water jet cutting, etc. After cutting, the surface of the microneedle and the residue on the cutting edge can be cleaned by pickling, etc., generally using hydrofluoric acid, nitric acid, etc. It is carried out with a mixed solution of sulfuric acid or a mixed diluted solution of hydrogen peroxide and water. the

The planar hollow microneedle structure prepared by the present invention is generally composed of a needle body array at the front end, a support body and a liquid storage tank at the rear end, the needle body is parallel to the direction of the substrate, and the shape is determined by the layout design. the

The planar hollow microneedle of the present invention can be widely used in transdermal drug delivery devices. The microneedle can enhance drug delivery efficiency by piercing the stratum corneum of the skin, especially for macromolecular drugs, and is a safe and painless transdermal drug delivery device. Method of administration. Due to the microchannel, the microneedle of the present invention can be partially integrated with the syringe for precise control of painless microinjection and body fluid extraction; at the same time, through the volume-adjustable reservoir, it can be combined with patches or implants to achieve drug delivery. The purpose of sustained release, so as to achieve more efficient, precise and long-term delivery of drugs. the

The invention combines various technologies such as micro-machining, traditional machining and cutting, reduces the difficulty of the process compared with the prior art, enhances the use reliability of the micro-needles, and can realize mass production. Specific advantages such as: 1. The introduction of diffusion welding technology makes the two substrates fusion bonded, which enhances the joint strength and sealing performance between the two flow channels, and improves the reliability of the use of microneedles; 2. Adopts laser cutting to form needles Compared with dry etching, it reduces the complexity of the process and saves the cost of preparing photolithographic plates; 3. Titanium-based materials are preferably used to ensure the hardness, toughness and biocompatibility of the microneedles, and The use of bulk titanium processing technology avoids the disadvantage of poor adhesion between the microneedle and the substrate and is easy to fall off; 4. The introduction of a four-inch titanium-based wafer makes it possible to combine traditional mechanical processing with MEMS processing technology, greatly expanding the preparation methods. the

Description of drawings

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

Fig. 2 is a schematic diagram of the flow channel pattern and microneedle morphology of the planar hollow microneedle of the present invention. the

Fig. 3 is a microneedle topography photo obtained by laser cutting, wherein B is an enlarged view of a needle shown in A. the

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. the

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 are performed to obtain a 200 μm thick four-inch titanium-based wafer polished on both sides or one side. The planar hollow microneedles were prepared according to the following steps using the titanium-based disc:

1. Form a microneedle channel

A double-sided polished titanium-based wafer was taken as the first titanium substrate 1, and a 15 μm-thick SU83010 photoresist 2 was spin-coated on one side of the polished surface, and left to stand for 24 hours. After pre-baking on a hot plate (from 45°C to 95°C for 2 minutes at every 10°C for 10 minutes, then cool down to room temperature naturally), expose on a four-inch chrome plate printed with microneedle flow channel patterns for 28s, and then perform a hot plate Post-baking (from 45°C to 95°C for 5 minutes at every 10°C for 1 minute, then naturally cool down to room temperature). Finally, use SU8 special developer to develop it for 8 minutes until the pattern of the photoresist plate appears completely, as shown in Figure 1a. Using ICP/RIE dry etching technology, chlorine-based gas is used to etch to a depth of 30 μm. The etching parameters are: coil power 300-500W, plate power 50W-200W, gas flow 30-70sccm, to form channel 3, as shown in FIG. 1b. the

2. Form cutting marks

On the polished surface of the other side of the first titanium substrate, evenly coat positive-type photoresist 4 with a thickness of 1 μm, align and expose for 4 seconds on a four-inch photoresist plate printed with a cutting pattern corresponding to the flow channel pattern one-to-one, and then Harden the film on a hot plate at 120°C for 1 minute, and develop until the graphics appear completely, as shown in Figure 1c. Immerse in a solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) for 1-2 minutes to etch out the cutting marks 5, as shown in FIG. 1d. Then immerse in an acetone solution to remove the photoresist, see Figure 1e.

3. Diffusion bonding

Take another single-polished (or double-polished) titanium-based wafer as the second titanium substrate 6, as shown in FIG. 1f, make its polished surface and the runner surface of the first titanium substrate 1 carry out diffusion welding bonding. Diffusion welding is performed in a vacuum environment of 1×10 ^-4 Pa, the temperature is about 1000-1200°C, and the pressure is kept for 1-2 hours. Among them, pressure is inversely proportional to time. The bonding pressure can reach above 18.18MPa.

4. Thinning and transferring cutting marks

Thinning CMP polishing is performed on the non-bonded surface of the second titanium substrate 6 to reduce its thickness by 150 μm, as shown in FIG. 1g. Afterwards, positive-type photoresist 7 is evenly coated on it, and the cutting pattern layout is used to align with the existing cutting marks on the back for exposure and development (see FIG. 1h ). Then wet etch the photoetched surface to achieve the purpose of transferring marks. The specific process steps are the same as the above step 2, and the cutting marks 8 are etched on the non-bonded surface of the second titanium substrate 6, as shown in FIG. 1i. The non-bonding surface of the first titanium substrate 1 is polished and thinned by CMP, so that the thickness of the entire bonding sheet reaches 100-150 μm, as shown in FIG. 1j . the

5. Cutting to form needle tip

Using an ultraviolet nanosecond or picosecond green laser to align the cutting mark 8 of the bonding sheet for microneedle cutting to form a needle body and a drug storage pool, and obtain a designed planar hollow microneedle. The preferred laser power is 3-50w. The obtained microneedle is soaked in a solution of HF:HNO ₃ :H ₂ O=1:1:30 (volume ratio) and pickled for 1 to 2 minutes to remove laser cutting residue and improve the smoothness of the surface.

In the above scheme, the flow path pattern and microneedle morphology of the prepared planar hollow microneedles are shown in FIG. 2 . The length of the needle body is 200-800 microns, the width is 20-80 microns, the thickness is 100-300 microns, and the needle point angle is less than 30°. Wherein, the inner channel has a depth of 30 microns and a width of 10-40 microns; the liquid storage tank is a cube with a side length of 1-5 mm. the

The metal substrate material used in this embodiment is 99.99% chemically pure titanium, and the microneedles are parallel to the direction of the titanium substrate substrate to form a single row of microneedle arrays (as shown in Figure 3), and the layout of the needles can be adjusted as required Set it yourself. the

As a metal with good biocompatibility, titanium material has irreplaceable advantages in making microneedles. First of all, titanium has enough hardness so that the needle tip can pierce the skin, and at the same time has good toughness, even if it is bent, it will not break and stay on the skin. Secondly, the penetration of titanium needles should not cause excessive skin reactions, and reduce possible inflammation and allergies in the administration area. However, as a metal material with strong corrosion resistance, the processing technology of titanium is difficult and the cost remains high, which has always been the biggest obstacle restricting its popularization and application. In order to manufacture titanium-based microneedles with higher reliability and greater practicability, we have combined various processing technologies such as micromachining, traditional machining and laser cutting, and prepared a kind of microneedle for transdermal drug delivery. The titanium-based planar hollow microneedle of medicine, the wafer-level preparation effectively improves the possibility of mass production, the diffusion welding technology significantly enhances the reliability of bonding, and the laser scribing method increases the flexibility of the microneedle structure. the

Claims (9)

1. A preparation method of planar hollow microneedles, comprising the following steps: 1) Define the microneedle flow pattern on one side of the first metal substrate to form a channel, and then define the microneedle pattern on the other side to align with the channel position to form a cutting mark; or, first on the first metal substrate Define the microneedle pattern on one side to form a cutting mark, and then align the microneedle pattern on the other side to define the microneedle flow channel pattern to form a channel; 2) Take a second metal substrate and bond it to the channel surface of the first metal substrate by diffusion welding; 3) thinning the non-bonding surface of the second metal substrate, and aligning and transferring the cutting marks on the first metal substrate to the non-bonding surface of the second metal substrate; 4) Thinning the non-bonding surface of the first metal substrate, and then cutting in alignment with the cutting marks on the second metal substrate to form a planar hollow microneedle. 2. The preparation method as claimed in claim 1, characterized in that: in step 1), the way of defining graphics is photolithography, laser marking or screen printing, and the way of forming grooves and cutting marks is to first metal substrate The chip is wet etched or dry etched. 3. The preparation method according to claim 2, characterized in that: in step 1), reactive ion etching technology is used to form the channel, and wet etching is used to form the cutting mark. 4. The preparation method according to claim 1, characterized in that: the first metal substrate and the second metal substrate are made of the same material, which is titanium, stainless steel, nickel or their alloys. 5. The preparation method according to claim 1, characterized in that: the thickness of the first metal substrate and the second metal substrate are both 50-2000 μm. 6. The preparation method as claimed in claim 1, characterized in that: Step 2) Diffusion welding is carried out in a vacuum environment of 1×10-4Pa, the temperature is 1000-1200°C, and the pressure is maintained for 1-2 hours . 7. The preparation method according to claim 1, characterized in that: wet etching or chemical mechanical polishing is used to thin the metal substrate in step 3) and step 4). 8. The preparation method according to claim 1, characterized in that: step 3) transferring the pattern of the cutting mark by means of alignment photolithography, laser marking or screen printing, and by wet etching or dry etching Cutting marks are formed on the second metal substrate. 9. The preparation method according to claim 1, characterized in that: the cutting method in step 4) is laser cutting, wire cutting, ion beam cutting or water jet cutting.

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