TW568790B - Hollow microneedle array and method for fabricating the same - Google Patents

Abstract

A method for fabricating hollow microneedle array is proposed, which includes preparing a wafer layer having a plurality of peaks with predetermined gradient for coating a photoresist layer on the surface of the peaks. Then, a set of vertical tubules whose tips are corresponding to the gradient of the peaks are defined on the photoresist layer to make the opening of the tips entirely submissive to the peaks. Thereafter, nanocrystalline electroplating metal material is electroformed onto the photoresist layer to fill into each vertical tubule. While the wafer layer and the photoresist layer have been removed, a hollow microneedle array is finished. Fabrication of microneedle array by means of semiconductor processes can provide the section of the tips of microneedle array with specific angle in a hollow design. Thereby, the needle can easily be penetrated into skin for beneficially sampling and performing transdermal delivery of drug, body fluid or biological molecules and the like.

Description

568790 V. Description of the invention (l) —- [Technical field to which the invention belongs] ... The present invention relates to a kind of penetrable epidermal layer (corneum) and epidermal layer (Epidermis) without harming the dermis (Dermis) Manufacturing method and structure of transdermal delivery device, especially a micron hollow needle array (Micrneenee Array) manufacturing method capable of minimizing tissue trauma and pain when injecting drugs and sampling body fluids from the skin And its structure. [Prior art]:

Among the various methods of drug delivery, the most common method is to inject the drug directly into the skin for subcutaneous injection (Intracutaneus InjectiQn). The skin structure of the human body consists of the epidermal layer (Corneum), the moisture-rich and intercellular fluid epithelium (Epidermis), which are composed of dead cells and aging cuticles from the outside to the inside, and then the dermis layer with blood vessels and nerves. ^, But the traditional needle size is large (generally larger than '50 & meters), in order to make the drug quickly enter the bloodstream, the needle penetration end is often deep into the skin bottom, resulting in damage to blood vessels and nerve endings and bleeding in patients and Pain. Especially in the treatment of diabetes (Diabetes), because the diabetic patients need to regularly test the blood glucose concentration and inject Tengdaosu, the number of subcutaneous injections per day is quite considerable, so if the medical profession cannot prescribe

When a painless, low-injection injection is made, patients are often afraid of injections that affect blood glucose control. To this end, Henry et. Al. Of Georgia Institute of Technology published in the literature a "Micromachined Needles for the Transdermal

568790 V. Description of Invention (2)

Del i very of Drugs ", as shown in Figure 6, the microneedle array (Microneedle Array) has a very small puncture end, with a diameter of about 15 to 40 standard medical gauges, and a length Between 5 and 100 microns; at the same time, this needle can also transmit various medical dosage forms including liquids, solutions, glues or hydrogels (Hydrage 1). As shown in the figure, the micron needle array is superior to traditional hypodermic needles in that the micron needle array can make extremely small needle penetration ends, so that when the drug is injected into the skin, it only penetrates the epidermal layer and part of the epithelial layer, and will not Damage the blood vessel and nerve dense dermis to prevent bleeding or pain during the injection. However, the "micrometer needle array (Micr ο need 1 e Array)" is limited to process technology, such as US Patent Nos. 6, 3 7 9, 3 2 4 "Intracutaneous Microneedle Array Apparatus" and 6,334,856 "Microneedle Devices and Methods of

Manufacture and Use thereof 'revealed that only three types of needles can be manufactured; as shown in Figure 7, the first type of needle (a) is a sharp solid needle, which has the advantage of good skin penetration, but the solid structure cannot provide The material passes, so it is difficult to sample or send medicine without practical value; in order to achieve the purpose of drug delivery, a hollow needle was developed later, as shown in (B) and (c) in Figure 7. Hollow needles include conical flat-shaped hollow needles (B) and round-shaped flat-shaped hollow needles (C). Although these two types of hollow needles are convenient for sampling and drug delivery, the needles are dull at the insertion end, so the needles are not easy to penetrate. Difficult to apply to the skin.

/ yv Description of the invention (3) ____ In order to improve the skin penetration, breakage, ceramics, or other non- ^ of hollow needles, the industry has tried to use silicon, stone, and the outer diameter is less than! 00 micron micro-materials' to produce needles made of materials less than 250 glazing and other materials Although: Yes: member J car train. Due to the poor ductility of silicon, quartz or silicon, the helmet method is easy to pierce the skin due to blood vessels, but the needle causes rejection and other problems. And if it is modified and easily brittle and remains in the human body, the production of micron hollow acupuncture can make metal materials such as needle rattan brocade alloy and other metals easily cause human allergies. Good ductility, but buried in Subcutaneously, if the needle needs to be longer on the surface of the needle, the patient's acupuncture site will be uncomfortable. The recorded ions and ions are often eye-catching, such as the literature shows that all metal towels will not produce discomfort symptoms. "Refers to biocompatible: day;: highest in the human body), the first is platinum,; = matabimy to platinum Or gold, the price is 5, f: = use only: the whole platinum or gold, to improve the compatibility of the needle for surface plating -φμ, human body.

…, And, with traditional electric money methods (such as D gold layer, each particle on the surface of the coating (referring to white: c pm gold or grain size), the size is 1 gold and; s gold Particles) have gaps, and can allow the surface of the object to be plated (^ β-conducting grains and crystal grains to pick up male Xiongshan Ni nickel needles). 'Only by adding 2 of the platinum or gold layer Therefore, in order to prevent patients from implementing: r :; high., And to solve needle skin penetrability, drug transmission, blood or pain, 1 to find power, material ductility, and

568790

V. Description of the invention (4) Micron hollow needle array system for the problem of biological phase valley sex temple and filial piety problem [Content]: The main purpose of the present invention is to design the needle piercing end for skin benefit and provide body fluids or drugs The structure of transmission. There is an urgent need to develop a method that can solve the above problems. Provided are a method for manufacturing a micron hollow needle array with an oblique cut angle and a skin that can be easily penetrated into the skin during injection.

Another purpose of this month is to provide a denser grain arrangement of the gold-plated layer to reduce the grain pores between adjacent gold particles, avoid nickel ions from drilling the pores on the surface of the plated object, and improve the biological phase of the needle. Manufacturing method and structure of capacitive (Biocompatabi 1 1 ty) micron hollow needle array. Still another object of the present invention is to provide a micron hollow needle array manufacturing method for avoiding bleeding, pain and tissue damage during percutaneous injection of patients, and reducing patients who frequently need needle injections because of psychological disturbances that interfere with the progress of treatment. Its structure.

In order to achieve the above and other objectives, the micron hollow needle of the present invention can provide related drugs, bodily fluids or other biological molecules (Biological Molecule) for percutaneous transmission without harming the dermis (blood vessels and nerves are densely packed in the dermis). Sampling to prevent bleeding or pain during subcutaneous injections, and to reduce the needle's tissue damage to the injection site. The micron hollow needle is a microneedle array formed by connecting a plurality of upright tube holes. The upright tube hole has an opening that contacts the skin, supports the opening and provides adjacent openings.

568790 V. Description of the invention (5) The bottom of the connected pipe and the core portion penetrating the opening and the bottom of the pipe, wherein the front end of the opening forms a sharp oblique angle, and the oblique angle intersects the horizontal plane by a preset angle. However, the micron hollow needle is fabricated in an Array configuration. The manufacturing method includes the following steps: preparing a wafer layer on which a plurality of peaks with a predetermined inclination are formed; and coating the surface of the peak A money stop layer (Etch Stop) or a seed layer; a first photoresist layer is covered on the resist layer; the first photoresist layer is developed to define a plurality of upright tube holes, the tube_ The front end of the hole is formed in accordance with the inclined surface of the peak, so that the opening surface of the tube hole close to the wafer layer completely fits the resist layer; a second photoresist layer is coated on the surface of the first photoresist layer and developed. So that after the second photoresist layer is peeled off, the thickness of the first photoresist layer at the core of the upright tube hole is greater than the thickness of the first photoresist layer outside the tube hole; Nano-grain electroformed nickel) to the first photoresist layer to fill and connect the vertical tube holes; and remove the wafer layer, the resist layer and the first photoresist layer to form a metal needle array. The method for manufacturing a micron hollow needle array according to another embodiment of the present invention also uses semiconductor process technologies such as wafers and photoresist coating to define the inclination of the front end of the needle array. The difference lies in the formation of the metal needle array, not directly The nano-grain electroformed metal is filled with a photoresist layer, but the formed upright tube hole is turned into a master mold, and then the nano-grain metal is electroformed into the master mold.

17163 Institute of Industry and Technology.ptd Page 11 568790 V. Description of the invention (6) The process method includes the following steps: preparing a wafer; coating a photoresist layer on the wafer, and using a gray scale mask, etc. The photoresist layer is made of a plurality of peaks with a predetermined inclination; the photoresist layer is etched vertically to define a plurality of opening mask hollow riser hole arrays with a predetermined inclination; the hollow riser hole array is flipped to form a female mold Eroding the hollow riser hole array; and electroforming a nano-grain electroformed metal to the master mold to form a metal needle array after demolding. In addition, the other two embodiments of the method for manufacturing a micron hollow needle array of the present invention use a rapid prototyping technology (Rapid Pr 〇t 〇typing) or a laser cutting method (Laser Cu 11 ing) to define the resin into a complex number Hollow opening tube hole array with a predetermined inclination of the opening masks, and then mold the vertical tube holes, and then dissolve the resin with a solvent after the master mold is formed; thereafter, the nano-grain metal is cast into the master mold by an electroforming method. , Can also form a metal needle array. In order to avoid the human allergy caused by the micron hollow needle array made of nano-grain electroformed nickel, the surface of the metal needle array completed according to the above manufacturing method can be coated with a layer of nano-grain electro-bonded gold (such as platinum, gold and its alloy, etc.). Or dip pp ng on the surface of the needle array-a layer of biocompatible polymer to form an isolation layer to block the release of metal nickel on the surface of the needle array. The nanocrystalline electroforming method is used to make the bond gold layer. The metal grain size is very small, and the grain arrangement is extremely dense. Therefore, compared with the traditional electroplating method, the nanograin electroforming technology can reduce the grain size. hole

17163 Institute of Industry and Technology.ptd Page 12 568790 V. Description of the invention (7) Gap to avoid the release of nickel ions under the gold plating layer to cause biocompatibility problems. On the other hand, the semiconductor needle technology is used to design the microneedle array's needle penetration end into an oblique cut angle, which can easily penetrate the skin during injection, and the hollow needle can also provide a fluid substance. A delivery channel for the transdermal delivery and sampling of drugs, body fluids, or other biomolecules, enabling patients to perform injections without feeling pain and bleeding. [Embodiment]: The following is a detailed description of the manufacturing method and structure of the Hollow Microneedle Array of the present invention with specific embodiments and the accompanying drawings. However, the following drawings only briefly illustrate the elements related to the embodiments. Numbers and types 'Those with the same elements between the drawings are given the same reference number 7Γ: 〇' The micron hollow needle array of the present invention provides related drugs, body fluids or other organisms without harming the blood vessels and nerves of the dermis. Molecules (Bi0gicai Molecule) are transdermally transported and sampled to avoid 77 stigmata temples: day: bleeding or pain occurs, it and reduce the needle to the injection part; new: round damage. The micron hollow needle is an array of micron needles (Micr ο need 1 e Aray) which is upright, and the literary liter rises / forms -JL-. The vertical camp hole has an opening that contacts the skin , The bottom of the tube supporting the opening / connecting the mouth, and the opening through the opening ";;; the supply is formed adjacent to the opening, wherein the front end of the opening forms a pointed ^. Of & ~ Intersect with the horizontal plane-preset angle. Too sharp bevel ’and that bevel

568790 V. Description of the invention (8) ^ ~ The micron hollow needles are manufactured in an array (Array) configuration, that is, the micron hollows are described by the 1A to 1 garden, the 3rd plant 3H diagram, the 4th diagram, and the 5F diagram. Various aspects of the manufacturing method of the needle array ^ to Example 0 First embodiment: As shown in the first level 1BS1 / jin, a wafer layer 1 (wafer) is prepared. It is made of gallium and other materials f, which has a crystal plane 10; a plurality of v-grooves 1 1 (V-groove) are opened on the crystal plane 10 by etching or abrasion. An inclined surface 110 having a predetermined angle is maintained between the horizontal planes. The angle of the inclined surface 10 is between 15 and 60 degrees. Taking this embodiment as an example, it is better to use the characteristics of the arrangement of silicon crystals as shown in Fig. 丨 β. The inclined angle of the etching is 5 4 · 7 4 degrees. Then, as shown in FIG. Ic, a conductive layer 2 (such as a seed layer) made of a metal material is deposited on the surface of the wafer layer 1 by sputtering or electroless plating method, or formed. A plasma etching etching stop layer 2 (Etch Stop), wherein the thickness of the conductive layer 2 or the etching stop layer 2 is preferably not to affect a predetermined inclination angle of the V-shaped groove. Next, as shown in FIGS. 1D and 1E, a photoresist layer 3 (referred to as the first photoresist layer 1 in this embodiment) is coated on the surface of the wafer 1 covered with the conductive layer 2 or the resist layer 2. ), The photoresist layer 3 may be composed of a dry film, a wet film, and other materials. In this embodiment, a negative photoresist (Negative photoresist) is preferred, and its thickness is greater than 150 micrometers. Thereafter, as shown in FIG. 1E, exposure and development are performed on the photoresist layer 3.

568790 V. Description of the invention (9) In the process of shadowing, etc., a plurality of upright tube holes 40 are formed by defining the position of the tube wall of the micron needle array 4 to form a plurality of upright tube holes 40. The front end of each upright tube hole 40 conforms to the V-shaped groove 1 1 inclined The surface 1 1 0 is opened so that the opening surface 4 0 of the tube hole 40 close to the wafer layer 1 completely adheres to the surface of the conductive layer 2 or the corrosion resistance layer 2. Taking this embodiment as an example, the upright tube hole 40 of the present invention is opened into a hollow shape. In addition to the tube wall 40 1 itself being eroded for metal filling in the subsequent electroforming process, the tube core portion 40 and the tube hole The photoresist layer 3 is distributed outside 40, and the thickness of the photoresist layer 3 at the core is the same as the thickness of the photoresist layer 3 outside the tube hole 40. Then, as shown in Figs. 1F and 1G, a second photoresist layer (not shown) is coated on the surface of the photoresist layer 3 and exposed and developed to reduce the photoresist layer outside the tube hole 40. The thickness of the photoresist layer 3 of the tube core portion 402 exceeds the surface of the photoresist layer 3 outside the tube hole 40. After that, the second photoresist layer is etched and reused, such as nano-grain (N a η ocrysta 1 1 ine) electroformed nickel, nano-grain electroformed cobalt, nano-grain electroformed nickel-cobalt alloy, etc. Nano-grain electroformed metal 5 fills the photoresist layer 3 so that the hollow upright pipe hole 40, the pipe wall 401, and the outer surface of the pipe hole 40 are formed with nano-grain electroformed metal 5; The thickness of the photoresist layer 3 of the part 4 2 is higher than that of the photoresist layer 3 outside the tube hole 40. Therefore, when the nano-grain metal is electroformed, the core part 4 2 will not cover the electroformed metal 5. Cover to ensure that the core portion 4 2 of the micron hollow needle 4 is unobstructed. Furthermore, as shown in FIG. 1, the wafer layer is completely etched away, and the photoresist layer is dissolved with a developer to completely expose the nano-grain electroformed metal 5, but if an upright tube is found after electroforming When the tube core 40 of the hole 40 is blocked, a grinding step may be added to expose the tube hole 40 again to make a micron hollow needle array 4.

17163 Industrial Research Institute.ptd Page 15 568790 V. Description of the invention (ίο) ^ ~ -——-- As shown in Figure 2A, the Nile a 轺 + + head array is used to improve its biocompatible nickel rice. Hollow needles form a layer on the surface of the needle array 4 for weekdays: after the above clothing is formed, another warehouse, gold alloy, platinum alloy, or KK ^; grains, cast gold 6 (such as pure gold, white (Dipping) coated with a layer of biological phase A polymer with good capacitance, a free layer of nickel ions. Applicable types of polymer include stone rubber (JS ^ llcone Rubber), polyimide turtle (Polyurethane), and perfomer polymer (PerflU0rinated polymer) And other materials. The nano-grain electroforming method is used to make the gold-plated layer 6. As shown in Figure 2β, the obtained metal grains have a small particle size (usually less than 100 nanometers (nm)), and the particle arrangement is extremely dense ( As shown in (a) and (b) of the figure, (a) represents the metal grains obtained by the conventional electroplating method, (magic means the grain I, the rice grains are electroformed metal grains); therefore, compared with traditional plating Method, the nano-grain electroforming technology can reduce the grain pores and avoid minerals (such as nano-grain electro-cast nickel needle arrays 4) under the gold plating layer, and nickel ions will be released and the patient will be uncomfortable to overcome The lack of inadequate biocompatibility of the traditional gold deposits. ^ Furthermore, as shown in Figures 2A and 2B, the semiconductor chip technology is used to design the puncture end of the microneedle array 4 into an oblique cut angle. The needle can be easily penetrated into the skin, and the hollow needle design can provide a transmission channel for fluid substances, and provide percutaneous transmission and sampling of drugs, body fluids or other biomolecules, making the needle more practical value. Agriculture _: ^ _ _ 实 _ 例 Example: Figures 3A to 3H show the micron of the present invention Hollow needle array system

568790 V. Description of the invention (11) Another embodiment of the manufacturing method. This method also uses semiconductor process technologies such as wafers and photoresist coatings to define the inclination of the front end of the needle array. It is different from the previous embodiment in that the metal needle array is formed in a way that does not directly use nano-grain metal. After filling the photoresist layer, the formed upright tube hole is turned into a mother film, and then nanometer grain electroformed metal is reused and cast into the mother film. The following is a detailed description of each step of the manufacturing method of the present invention in conjunction with Figures 3A to 3: First, as shown in Figures 3A and 3B, a wafer layer 1 is prepared, and the wafer layer 1 has a crystal plane 10, The wafer layer 1 may be made of silicon, silicon dioxide, or other materials, or replaced by glass, ceramic, or the like. A photoresist layer 3 having a predetermined thickness is coated on the crystal plane 10, and the photoresist layer 3 may be made of a dry film, a wet film, or other materials. In this embodiment, a dry film is preferred, and the dry film covers The thickness is between 100 microns and 300 microns. Next, as shown in FIG. 3C, a part of the photoresist layer 3 is removed by developing with a Gray Scale Mask or a vertical moving exposure mechanism (Elevating Exposure Sy stem), and the remaining portion is gradually raised from the crystal plane 10 gradually. The photoresist layer 3 is formed at an oblique angle, so that the inclined surface 300 having a predetermined angle is maintained between the photoresist layer 3 and the crystal plane 10. The angle of the inclined plane is between 15 and 60 degrees. Then, as shown in FIG. 3D, a vertical unidirectional etching method is used to define the extreme 1y Anisotropic Etch, such as the Inductively-coupled-plasma (ICP) #etching technology. Micron needle array 4 tube wall position to form an upright tube hole array 4 with a plurality of upright tube holes 40 (which is completely consistent with the micron hollow needle array 4 type, so it is represented by the same component symbol), the upright tube hole array 4 is an opening with a predetermined bevel at the front end of the pipe hole 40

17163 Industrial Research Institute.ptd Page 17 568790 V. Description of the invention (12) 41, and the upper part 42 which supports the opening 41, wherein the bottom resistance layer connected to the upright adjacent pipe hole 40 3, and the tube bottom 42 is formed by a hole; the opening 41 of the car column 4 is formed by the light gray scale mask, vertically moved, and I f is formed by a wafer layer 1. However, the above-mentioned techniques are all known, so here again, the icp plasma erosion described by j here will not be repeated here.

After that, as shown in Figures 3E and 3F + V 6 + Ancient > μ # Badness' uses the upright official hole array 4 made of wafer layer 1 and photoresist layer 2 as the core θ 1 and nine resistance layer tables (Electroforming) in today's rCJ * 〇Lld Core), using electroforming technology, outside the plate to make a dipironic magnetic 7; after the mother mold 7 is formed, the hydrogen layer A mother branch round layer 1, complex Solve with a developer?丨 Said = (Acetate) The bottom crystal of the upright tube hole array 4 is turned over and the photoresist layer 3 of the opening portion 41 is formed so as to completely conform to the upright tube hole array. Electroforming: mold 7, # 内 shaped pattern out of the hole 40 outside the mother die plane 'and the height of the mother die of the tube core portion 40 2 is high, as shown in FIG. 3G (shown as h in the figure). A master mold 7 (shown in FIG. 3F) of the upper family 1 is electroformed with a nano-grain electroforming method to form an array of upright tube holes 4 formed by m coating, and then the nano-grain electroformed cobalt and Gao Mi ^ ♦ gen 5 (such as nano-grain electroformed nickel, micron hollow needle array: here ?, Cobalt alloy, etc. are completely in accordance with the upright tube hole in this place ^ It should be mentioned that due to the electroformed mother Die nano-granular electroformed metal 5 scales ^ # pattern is turned into a mold "®this" when the height exceeds the tube hole 4 is called the second mother, due to the female mold yv of the core part 4 ° 2 ^ ^ ^ ^ ^ The plane of the master mold can prevent the hollow part of the needle from being blocked due to the stress of the electroformed metal. Then, as shown in Figure 3H, the surface of the micron hollow needle array is electrically charged.

Institute of Industry and Technology.ptd Page 18 568790 V. Description of the invention (13) 鍀 One layer of nano-grain electroformed gold 6 (including pure gold, gold alloy, platinum, platinum alloy or K gold) 'or choose dipping method Coat the surface of the micron hollow needle array 4 with a good biocompatible polymer such as stone gum, polyurethane or perfluorinated polymer to block the nickel on the surface of the needle array 4 The ions are released, and the process steps of the micron hollow needle array 4 are completed. Compared with the foregoing embodiment, a photoresist layer produced by gradually elevating a gray scale mask (Gray S ca 1 e M ask) or a vertical moving exposure mechanism (Elevated Exposure System) can also form a predetermined tilt angle The inclined surface inclines the open end of the tip of the microneedle array by about 15 to 60 degrees to produce the same effect as the v-shaped groove of the foregoing embodiment. Third Embodiment: _ Figures 4A to 4F show the third embodiment of the method for manufacturing a micron hollow needle array of the present invention. This embodiment and the following fourth embodiment are the same as those of the second embodiment. Similarly, an array of at least straight riser holes is formed in advance, and then an electroformed master mold is made by using the riser bore array as a mold core, but the difference is that the riser bore array of this embodiment is based on rapid prototype technology (Rapid (Prototyping) curing resin to replace the semiconductor process of covering the photoresist layer on the wafer surface. This method includes the following steps: First, as shown in Figure 4A, rapid prototyping is used to apply high energy such as laser or ultraviolet light. The light beam 8 irradiates a thermoplastic resin such as epoxy, silicone, polyester resin, or polyphenolic acid resin, and the resin is cured from curing to hardening. Erect

568790 V. Description of the invention (14) T of the hole array 4 Next, if thermosetting resin is used, most of the connection systems are formed with a predetermined range of 15 to 60 degrees, and if column 4 is the mold core, the outer mold is made. (The thickness of the master pattern of the forming pattern with the acid-base dissolving part is shown in excess). Then, if the hollow core needle of the meter is copied on the female mold, the polycrystalline grain electroformed metal with good line properties [see the truth — and the manufacturing method of Figure 5A is similar, the rows are first used as the core core for the example. , At the bottom of the BU 4 2. As shown in Figs. 4B and 4C, the laser 8 is continuously and rapidly formed above the tube bottom 42 of the upright tube hole array 4 to integrate the opening 41 of the bottom 42 of each tube. However, the cut angle of the inclination angle of the front end of the opening 41, and the angle of the inclined cut angle is between that shown in FIG. 4D. The upright tube hole array made of hardened resin is electroformed on the mold. Core ί 2 ί 7 'After the mother mold 7 is formed, visit again as shown in Figure 3E: ",,," The resin is dissolved, so that the electroformed mother mold 7 meat and the upright tube?丨 _ From the bamboo / electric bismuth mother branch γ inside the tube hole outside the mother 2: 4 completely, together, | the core of the tube, a certain distance from the plane (as shown in Figure 4F of the household, ~ upright tube array The nano-grain electric prayer method is used on the surface of the electroformed row 4 of the electroformed column 4 'to restore the formed micro-composite material after demolding, and the nano-grain electro-gold or bio-phase locust umbrella is The isolation layer is used to complete the nano hollow needle array of the present invention. The first to fourth embodiments are shown in the fourth embodiment. The micro hollow needle array of the present invention is at least-this embodiment and the third embodiment described above are fabricated in phase The perch riser hole array 'then uses the riser hole array in the two upright female molds. However, this embodiment is different from other solid s-hole arrays by laser cutting method.

17163 ITRI, ptd

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568790 V. Description of the invention (15) (L a s e r Cu 11 i n g) The whole substrate material is melted into a predetermined shape, and then the mold is turned over. The manufacturing method includes the following steps: As shown in FIG. 5A, an organic material substrate 9 is prepared, and the material of the substrate 9 may be made of poly (polycarbonate) or other hot-melt materials. In this embodiment, the polycarbonate substrate 9 is used as the opening and closing material of the vertical tube hole array, and laser cutting is used to perform a unidirectional vertical cutting (the laser 8 is etched from the top of the substrate 9 to the Below). Then, as shown in Figs. 5B and 5C, laser cutting is continued on the surface of the substrate 9 to define at least one upright hole array 4 of upright tube holes & 0, the upright tube holes The array 4 is formed by an opening at the front end of the tube hole 40 and supporting the opening portion 41 and providing an adjacent upright tube hole 40 connection: 邛 42. The opening portion 41 is not right with the tube bottom 4; :::: oblique angle The stomach is cut, so that the second inclination of the oblique cut angle is made out of the mold-electric prayer master 7; wait for the master 70% ;. _ ^ No, the molding pattern formed by the I carbonate substrate 9 obtained by the etching method is used to obtain the internal molding pattern of the electroformed master mold 7 and the upright tube hole ^ ^ eight, and the thickness of the core mold core mold Wang Ran kissed beyond the tube hole (shown as h in the figure).丨 The mother branch is separated by a moment, as shown in FIG. 5F, using the nano-grain electroforming method to copy the upright tube hole array 4 'on :: after demolding and forming a% unhollowed needle array 4 The surface is covered with a layer of nano-grain electroforming 纟 6 or biological times

17163 Institute of Industry and Technology.ptd Page 21 568790 V. Description of the invention (16), ___ Polymer materials with good capacitance as the isolation layer, the micron hollow needle array made of this and grain electroformed metal is completed. It is only clear that the resin material is made with nanometers and Rapid Prototyping; or the laser cutting method is used to change the substrate surface to the array of cured tube holes, and the open ends of the tube holes can be directly formed into a predetermined shape. The inclination of the n-cut is made by electroforming the front end of the hollow needle, which can also produce an inclination angle of 15 to 60 degrees, so as to achieve the same effect as the aforementioned semiconductor manufacturing method.

The above are only used to illustrate the specific implementation examples of the present invention, and are not intended to limit the implementable scope of the present invention. 'Those who are familiar with the technology can complete it without departing from the spirit and technical ideas disclosed by the present invention. All equivalent modifications or changes shall still be covered by the scope of patent application mentioned later.

17163 Industrial Research Institute

Page 568790 Brief description of the drawings [Simplified illustration of the drawings]: Figures 1 A to 1 show the first embodiment of the manufacturing method of the micron hollow needle array of the present invention; Figure 2A shows the micron hollow according to the present invention A perspective view of a micron needle made by a needle array manufacturing method and electroplated with nano-grain electroformed metal. Figure 2B is a schematic cross-sectional view of Figure 2A along the section line 2B-2B; Figures 3A to 3D show the present invention. The second embodiment of the method for manufacturing a micron hollow needle array; Figures 4A to 4F show the third embodiment of the method for manufacturing a micron hollow needle array of the present invention; The Figures 5A to 5F show the micron hollow needle array of the present invention The fourth embodiment of the manufacturing method; FIG. 6 is a high-magnification view of an electron microscope of a conventional micrometer needle array; and FIG. 7 is a simple schematic comparison diagram of the needle penetration ends of three conventional micrometer needles. 1 Wafer layer 10 Crystal plane 11 V-shaped groove 110 V-shaped groove inclined surface 2 Conductive layer (resistance layer) 3 (first) photoresist layer

17163 Industrial Research Institute.ptd Page 23 568790 Brief description of the drawing 3 0 Photoresist inclined surface 4 micron hollow needle array 4 0 Upright tube hole 400 Opening surface 401 Tube wall 40 2 Core part 41 Opening part 42 Tube bottom 5 Nai Rice grain electrojunction metal 6 Nano grain electroformed gold 7 Electroformed master 8 Local energy beam 9 Organic material substrate

17163 ITRI.ptd Page 24

Claims (1)

568790 6. Scope of patent application 1. A micron needle array (Micr ο need 1 e Array) manufacturing method for transdermal transmission, the method includes the following steps: preparing a wafer layer on which a plurality of predetermined A peak portion of the inclination; covering the peak portion with a first photoresist layer; developing the first photoresist layer to define a plurality of upright tube holes, the front end of the tube hole is formed in accordance with the inclined surface of the peak portion, and The opening surface of the tube hole close to the wafer layer is completely adhered to the peak portion; a second photoresist layer is coated on the surface of the first photoresist layer and developed, so that after the second photoresist layer is peeled off, the The thickness of the first photoresist layer in the core portion of the upright tube hole is greater than the thickness of the first photoresist layer outside the upright tube hole; a nano-grain electroformed metal is filled on the first photoresist layer to form a metal A needle array; and removing the wafer layer and the first photoresist layer. 2. The method for manufacturing a micron needle array according to item 1 of the patent application scope, further comprising forming an isolation layer on the surface of the needle array after the metal needle array is formed. 3. The microneedle array manufacturing method according to item 2 of the patent application scope, wherein the isolation layer is formed by electroforming with a nano grain electroformed gold, and the material of the nano grain electroformed gold is selected from One of the groups of pure gold, platinum, gold alloy, platinum alloy and K gold. 4. The microneedle array manufacturing method according to item 2 of the patent application scope, wherein the isolation layer is formed by dipping method (D i pp i ng) and is selected from silicon rubber 17163 Industrial Research Institute. Ptd page 25 568790 One of the materials group of patent application scope (filicone rubber), polyurethane (Polyurethane) and perfluorinated polymer (Perfluorinated polymer). 5. The method for manufacturing a micron needle array according to item 1 of the application, wherein the micron needle array is designed in a hollow shape (Ho 1 1 ow). 6 · The microneedle array manufacturing method according to item 1 of the patent application scope, wherein after the wafer layer forms a peak portion, a seed layer is coated on the surface of the peak portion. 7. If the application of the microneedle array manufacturing method of the first item of the scope of application: "The wafer layer forms a peak portion I, and a layer (Etch Stop) is formed on the surface of the peak portion. 8. The micron needle array manufacturing method of item 1 in Zhongli range. The inclination of radon is between 15 and 60 degrees. 9 · As in the patent application section μ, the method of manufacturing a micron needle array of # ΐ 1 item ρ, — the photoresist layer is a negative photoresist. ive 1 0 · As described in the patent application, the method for manufacturing a micron needle array of the first half of this term is (nm). ”Said that the grain size of the grain-to-metal conversion is less than 100 nanometers 1 1 · As shown in the patent application chart, the method of manufacturing micron needle arrays of the nanometer grain U is 12. If the scope of the patent application is 2 Nano-grain electroformed nickel 13. For example, a method for manufacturing a micron needle array of scale metal-nano-grain electroformed 1st item is applied. 17163 Industrial Research Institute.ptd Page 26 568790 6. In the scope of patent application, when the nano-grain electroformed metal is overlaid on the photoresist layer of the core of the upright tube, it is removed by grinding. 14. A method for manufacturing a micron needle array (Micr ο need 1 e Array) for percutaneous transmission, the method includes the following steps: preparing a wafer layer; and coating a photoresist layer on the wafer layer, The photoresist layer is formed into a plurality of peaks with a predetermined inclination; the peaks are etched to define a plurality of upright tube hole arrays whose opening surfaces conform to the inclination of the peaks; Forming a master mold; etching out the upright tube hole array; and electroforming a nano-grain electroformed metal to the master mold to form a metal needle array after demolding. 15. The method for manufacturing a micron needle array according to item 14 of the patent application scope, further comprising forming an isolation layer on the surface of the needle array after the metal needle array is formed. 16. The method for manufacturing a micron needle array according to item 15 of the scope of patent application, wherein the isolation layer is formed by electroforming to form a nano-grain electroformed gold, and the material structure of the nano-grain electroformed gold is One selected from the group consisting of pure gold, platinum, gold alloy, platinum alloy, and K gold. 17. The method for manufacturing a micron needle array according to item 15 of the scope of patent application, wherein the isolation layer is formed by dipping method (D i pp i ng) and is selected from the group consisting of, for example, Silicone Rubber and Polyurethane. ) And Perfluorinated polymer 17163 Industrial Research Institute.ptd Page 27 568790 6. Scope of patent application One of the groups. 18. The method for manufacturing a micron needle array according to item 14 of the scope of patent application, wherein the micron needle array is designed in a hollow type (Ho 1 1 ow). 19. The method for manufacturing a micron needle array according to item 14 of the scope of patent application, wherein the peak portion of the photoresist layer is formed by gradually increasing the height by using Gray Scale Mask technology. 20. The microneedle array manufacturing method according to item 14 of the scope of patent application, wherein the peak portion of the photoresist layer is formed by gradually elevating the vertical moving exposure mechanism (Elevating Exposure System). 2 1. The microneedle array manufacturing method according to item 14 of the scope of patent application, wherein the inclination of the peak portion of the photoresist layer is between 15 and 60 degrees. 2 2. The method for manufacturing a micron needle array according to item 14 of the scope of the patent application, wherein the peak portion of the photoresist layer defines a tube with a vertical tube hole using an extremely unidirectional #etch method (EX treme 1 y Anisotropic Etch). Wall position. 2 3. The microneedle array manufacturing method according to item 22 of the patent application scope, wherein the polar unidirectional etching method uses an inductively-coupled-plasma (ICP) I etch technique. 24. The microneedle array manufacturing method according to item 14 of the scope of patent application, wherein the master mold is formed by an electroforming method (Electroforming). 25. The microneedle array manufacturing method according to item 14 of the scope of patent application, wherein the grain size of the nano-grain electroformed metal is less than 100 nanometers (nm). A method for manufacturing a micron needle array in the range of item 14 which 17163 Industrial Research Institute.ptd Page 28 568790 6. In the scope of patent application, the nano-grain electroformed metal is a nano-grain electroformed nickel. 27. The microneedle array manufacturing method according to item 14 of the scope of patent application, wherein the nano-grain electroforming metal is a nano-grain electroforming. 2 8. — A method for manufacturing a micron needle array (Micro Array need 1 e Array) for percutaneous transmission, the method includes the following steps: irradiating a resin with a high-energy beam to form at least a straight tube hole array, the vertical tube hole array A plurality of vertical tube holes with predetermined inclination openings are defined above; flipping the vertical tube hole array to form a master mold; etching the vertical tube hole array; and electroforming a nano-grain electroformed metal to the mother Mold to form a metal needle array after demolding. 29. The microneedle array manufacturing method according to item 28 of the patent application scope, further comprising forming an isolation layer on the surface of the needle array after the metal needle array is formed. 30. The microneedle array manufacturing method according to item 29 of the patent application scope, wherein the isolation layer is formed by electroforming with a nano-grain electroformed gold, and the material structure of the nano-grain electroformed gold is One selected from the group consisting of pure gold, platinum, gold alloy, platinum alloy, and K gold. 3 1. The microneedle array manufacturing method according to item 29 of the patent application scope, wherein the isolation layer is formed by a dipping method and is selected from the group consisting of, for example, Silicone Rubber and Polyurethane. And perfluorinated polymer (Perfluorinated polymer) and other materials group. 17163 Industrial Research Institute. Ptd Page 29 568790 6. Application scope of patent 3 2. For example, the method of manufacturing micron needle array of the 28th item of patent application 'in which the micron needle array adopts a hollow type (Ho 1 1 ow) design. 33. The microneedle array manufacturing method according to item 28 of the patent application scope, wherein the high-energy beam is a laser. 34. The method for manufacturing a micron needle array according to item 28 of the scope of patent application, wherein the inclination angle of the upright pipe hole is between 15 and 60 degrees. 35. The microneedle array manufacturing method according to item 28 of the patent application scope, wherein the resin is selected from the group consisting of epoxy, silicone, polyesters, and polyphenolic acid resins. i η) and other thermoplastic resins. 36. The microneedle array manufacturing method according to item 28 of the patent application scope, wherein the upright tube hole array is manufactured by Rapid Prototyping technology. 37. The microneedle array manufacturing method according to item 28 of the patent application scope, wherein the resin is a polycarbonate resin substrate. 38. The method for manufacturing a micron needle array according to item 28 of the patent application scope, wherein the 'upright tube hole array is made by laser cutting technology. 39. The microneedle array manufacturing method according to item 28 of the patent application scope, wherein 'the master mold is formed by an electroforming method (Electroforming). 40. The method for manufacturing a micron needle array according to item 28 of the scope of the patent application, wherein the grain size of each metal of the 4 nm grain size is less than 100 nm. 17163 Industrial Research Institute. Ptd Page 30 568790 6. Application for Patent Range (nm) 〇 4 1. The method for manufacturing a micron needle array as described in item 28 of the patent application, wherein the nano-grain electroformed metal is a nanometer Rice grain electroformed nickel. 42. The microneedle array manufacturing method according to item 28 of the patent application scope, wherein the nano-grain electroformed metal is a nano-grain electroformed cobalt. 43.—It can provide drugs, body fluids or other biomolecules (B i ο 1 〇gica 1 Μ ο 1 ecu 1 e) percutaneously without harming the dermis (blood vessels and nerves are densely packed in the dermis). The needle array for transmission and sampling includes: a hollow needle array formed by connecting a plurality of upright tube holes, the upright tube hole having an opening in contact with the skin, and a bottom of the tube supporting the opening and providing connection to adjacent openings In the structure, a sharp oblique angle is formed at a front end of the opening portion, and the oblique angle intersects a horizontal plane at a predetermined angle. 44. The needle array according to item 43 of the scope of patent application, wherein the upright pipe hole has a core portion that penetrates both the opening portion and the bottom of the pipe at the same time. 4 5. The needle array according to item 43 of the patent application scope, wherein the oblique angle is between 15 and 60 degrees. 46. The needle array according to item 43 of the scope of patent application, wherein a nano-grain electroplated platinum is formed on the outer surface of the upright pipe hole. 47. The needle array according to item 43 of the scope of patent application, wherein a nano-grain electromechanical gold is formed on the outer surface of the upright pipe hole. 17163 ITRI.ptd Page 31