JP2009061745A - Method of manufacturing microneedle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To manufacture microarrays stable in quality having no fracture at the tip end parts of a microneedles in large quantities by use of a biodegradable resin, further to precisely make metal molds for those. <P>SOLUTION: A method of manufacturing microneedles made of resin is obtained by making cast molds of PDMS having through holes corresponding to the required microneedles in good quality in large quantities, conducting transfer processing at a high temperature from a transition point to a melting point of a biodegradable resin, and releasing the resin at the vicinity of the transition point. Further, a method of manufacturing metal matrix is obtained to make the good-quality cast molds of PDMS in large quantities. Hence, the microneedles having high reliability in a product specification can be efficiently manufactured. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a method for manufacturing a microneedle. In particular, the present invention relates to a method for manufacturing a microneedle made of a biodegradable material.

As a method for transdermally administering a drug, generally, a liquid or ointment applied to the skin surface, or a patch-type transdermal administration preparation has been used. In the case of human beings, the skin is usually composed of a plurality of tissues including a stratum corneum having a layered structure having a thickness of 10 to 30 μm, an epidermal tissue layer having a thickness of about 70 μm, and a dermal tissue layer having a thickness of about 2 mm. .
The stratum corneum is layered on top of the skin and acts as a barrier to prevent the penetration of various drugs from the skin. In general, about 50 to about 90% of the skin barrier action occurs in the stratum corneum. The skin layer does not perform as much barrier action as the stratum corneum, but performs the remaining 10% or more barrier action. On the other hand, the dermis has an abundant capillary network near the junction between the dermis layer and the epidermis layer. Therefore, once the drug reaches the depth of the dermis, it travels through the capillary network and becomes deeper in tissues (hairs). Quickly spread to wraps, muscles, etc.) Then, the drug is diffused from the capillaries through the blood circulation throughout the body.

Today, various liquid / ointment coatings and patch-type transdermal preparations have been developed. However, due to the barrier action of the stratum corneum, the medicinal components are not so much absorbed. For example, even in the formulation of indomethacin transdermally administered, which is said to have high transdermal absorption efficiency, it is said that only about 5% of the total amount of indomethacin is absorbed percutaneously.
Therefore, as one of the methods for increasing the skin permeability of the drug, as shown in Patent Document 1, a microneedle (microphone needle or microsyringe) is used to locally destroy the stratum corneum and remove the drug. Attempts have been made to force administration to the dermis layer.
Since the microneedles used for this purpose only need to reach the dermis layer, the length of the needles is preferably 30 μm or more, and if there is a substrate necessary to support the needles It is said to be good. This microneedle does not hurt because it does not reach the dermis layer where the nerve ends are present. Therefore, there is an advantage that the drug can be administered without giving fear to children.

Various methods have been reported so far regarding methods for producing microneedles. However, most of them produce silicon, glass, and metal microneedles using a method such as etching of X-ray irradiation used when producing a semiconductor as shown in Patent Document 2. . However, in this manufacturing method, the manufacturing cost of the microneedles is high, and fragments of the microneedles remaining due to problems such as breakage damage the human body.
Therefore, in order to improve this, for example, in Patent Document 3, a master mold of a microneedle is produced using polymethyl methacrylate (PMMA), and metal mold is applied to the master mold to remove the master mold. Is making. A polymer material is heated and pressed against the metal mold to produce a target resin microneedle.
However, in the method of manufacturing a microneedle using such a non-through-hole mold, frictional stress is applied when the microneedle is taken out of the mold, and the tip portion of the microneedle is easily chipped. For this reason, it has been difficult to obtain a microneedle having a good quality and having no tip portion defect.

Therefore, Patent Document 4 shows that PDMS (polydimethylsiloxane), which is a flexible material, is used as a mold and a microneedle is manufactured using a photocurable polymer.
Further, Non-Patent Document 1 shows that PDMS was similarly used as a template, and microneedles were produced using polylactic acid and polyglycolic acid as biodegradable resins. However, since the PDMS mold is flexible, a method is adopted in which the resin is dissolved and poured into a non-through-hole mold under reduced pressure while avoiding pressure transfer to the resin.
The microneedle matrix for producing this PDMS mold is produced using SU-8 and polyurethane. However, in order to make a non-through-hole mold, many processes are spent on the processing of the tip of the microneedle as the processing of the mother die.
However, this PDMS mold is weak in strength and difficult to use repeatedly. Therefore, in order to manufacture a large number of microneedles, an amount of a PDMS mold that can handle the microneedles is required. Furthermore, in order to make a necessary amount of the PDMS mold, it has become necessary to make a microneedle matrix having high durability strength.
Thus, several improvements have been made regarding the production of microneedles for percutaneous absorption, and high quality ones have been made. However, since it is in a situation where a molten resin is poured into a desired microneedle by using a non-through-hole type mold, the cost is high and the operation becomes a high temperature (about 100 degrees). It is also difficult to knead into a needle.
Accordingly, a manufacturing method that can produce biodegradable resin microneedles at a relatively low temperature and facilitate the mixing of drugs has been demanded. Furthermore, there is a need for a microneedle that is inexpensive and can be disposable. The problem with microneedles is how to produce microneedles that are made of biocompatible materials and have a certain level of strength and durability, and that have no defects and are stable in quality. It is.
Furthermore, since such a microneedle is usually disposable, it is required to be inexpensive.

JP 2006-149818 A Special Table 2002-517300 Special table 2003-501163 Special table 2004-526581 J. et al. Controlled Release, 104, 51-66 (2005)

  An object of the present invention is to produce a Kenyama microneedle at low cost and on a mass production scale using a biodegradable material. More specifically, it is an object of the present invention to provide a manufacturing method with high standard reliability in which a drug can be mixed into a microneedle and the tip portion of the microneedle is aligned without being chipped.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors use a polydimethylsiloxane (PDMS) mold and use a biodegradable resin from the transition point (glass transition point) to the melting point. The manufacturing method characterized by carrying out transfer processing under reduced pressure in the above temperature range was found.
As shown in Non-Patent Document 1, the feature of the PDMS mold is rich in flexibility. Therefore, it can be easily detached from the microneedle, and the tip of the microneedle can be prevented from being lost. . Furthermore, in order to improve this effect, a device was devised in which all the microneedle molds were through-holes.
The characteristics of the present invention will be described in detail as follows.
(1) A microneedle is produced using a PDMS mold having a through hole:
In contrast to the case of a non-through hole, even in transfer processing under the same vacuum, unlike Non-Patent Document 1, it is performed at a temperature lower than the melting point of the biodegradable resin. Since the holes are blocked by the functional resin and the air cannot escape, the resin cannot sufficiently flow into the mold.
In the case of a non-through hole, when the resin is solidified at a low temperature and the resin is released from the mold, the air pool generated in the mold becomes a negative pressure, the mold cannot be released and the needle breaks.
By the way, in the case of the mold of the through hole of the present invention, it can be transferred to the resin at a lower temperature. Further, regarding the release from the resin, since it is a through hole, there is no negative pressure. Since the temperature is near the transition point, friction is suppressed. From these facts, the tip of the biodegradable resin microneedle obtained can be avoided.
(2) Transfer to the biodegradable resin is performed under reduced pressure in a temperature range lower than the melting point from the transition point:
When the melting point is higher than the melting point of the resin, the adhesiveness to the mold increases, and it becomes difficult to release the microneedle from the mold. Therefore, it is necessary to soften the resin (below the melting point) without melting the resin. When the resin is cooled and the microneedles are released from the mold, it is difficult to release the microneedles due to frictional resistance due to the surface roughness of the mold through hole. In order to avoid this and prevent breakage of the tip portion of the microneedle, the resin is released without being completely cured at a temperature in the vicinity of the resin transition point.

On the other hand, the mold made of PDMS has poor durability and is difficult to use after about 10 transfer processes. Therefore, in order to manufacture a large number of biodegradable resin microneedles, an efficient manufacturing method of a PDMS mold is required. In order to manufacture a large number of PDMS molds, a metal mold excellent in durability is required instead of a resin microneedle mold as in Non-Patent Document 1.
Thus, it is considered essential to manufacture highly accurate metal microneedles for manufacturing a PDMS mold. Accordingly, the present inventors have studied a method for manufacturing a metal microneedle using a metal plating technique, and have found several efficient methods.
As described above, by using the method for manufacturing a metal mold of a microneedle according to the present invention and the method for manufacturing a microneedle of a biodegradable resin, a microneedle having good quality and low cost can be mass-produced. We have found that this is possible and have completed the present invention.

The gist of the present invention is as follows.
[1] A method for producing a Kenyama microneedle made of biodegradable resin having the following shape,
(1) In order to fabricate the resin-made Kenzan-type microneedles, a polydimethylsiloxane (PDMS) mold having through holes (cylinders, cones, prisms, pyramids) matching the size of the microneedles is used as follows. To make,
a) 10 to 500 cylindrical, prismatic, conical or pyramidal holes having a size of about 50 to 200 μm in a silicon (Si) flat plate having a thickness corresponding to the length of a microneedle. Open,
b) Metal plating is performed on the Si device manufactured as described above, and the through hole and the surface of the device are covered and filled with metal.
c) Dissolving and removing the Si device to produce a metal needle mold of microneedles.
d) Apply and solidify PDMS resin in the form of a flat plate on the metal matrix to create a PDMS mold having through holes of the same type as the Si device.
(2) High-temperature transfer processing is performed on the biodegradable resin under reduced pressure using the PDMS mold.
(3) The temperature of the resin is cooled to near the transition point, and the resin is released from the mold.
A method for producing a Kenyama-type microneedle made of a biodegradable resin.
[2] The method for producing microneedles according to the above [1], wherein the metal plating is nickel plating or copper plating.
[3] The method for producing a microneedle according to the above [1] or [2], wherein the biodegradable resin is polylactic acid.
[4] Kenyama microneedle (1) The width of the base of the microneedle is 50 to 200 μm
(2) The length from the tip of the microneedle to the base is 30 μ to 2 mm
(3) The method for producing microneedles according to any one of [1] to [3] above, wherein the number is 10 to 500.

[5] A method for manufacturing a metal microneedle mold, using a Si flat plate having a thickness corresponding to the length of the microneedles, and a columnar or prismatic shape having a size of about 50 to 200 μm in a semiconductor process. , A method for producing a metal mother die comprising opening 10 to 500 conical or pyramidal through holes, and then selecting any one of the following five methods:
(1) The first method is as follows:
a) A Si flat plate having a through hole corresponding to a sword-shaped microneedle is thermally bonded to a non-porous Si flat plate on a plane having a smaller diameter of the through hole.
b) Sputtering or vacuum deposition of Ti and Pd on the surface of the opening of the Si device obtained by thermal bonding,
c) Metal plating is performed on a Si device coated with Ti and Pd, and the metal is coated and filled.
d) Dissolving and removing the Si device to obtain a metal microneedle matrix,
(2) The second method is as follows:
a) The Si flat plate having a through hole corresponding to the sword-shaped microneedle is combined with the non-porous Si flat plate obtained by sputtering Ti and Pd on the plane having the smaller diameter of the through hole.
b) Fixing the two Si flat plates so as not to be separated by a protective tape, and producing a Si device.
c) performing metal plating on the fixed Si mold, depositing metal from the bottom of the mold, and covering and filling the device with metal;
d) Dissolving and removing the Si device to obtain a metal microneedle matrix,
(3) The third method is as follows.
a) A UV curing agent is applied to the outer peripheral portion of a non-porous Si flat plate obtained by sputtering Ti and Pd, and UV is irradiated.
b) A Si flat plate having a through-hole corresponding to the sword-shaped microneedle and the non-porous Si flat plate are bonded together on a plane having a smaller diameter of the through-hole to produce a Si device.
c) Metal plating is performed on the hole surface of the Si device, metal is deposited from the bottom of the hole, and the surface of the device hole is covered with metal.
d) dissolving and removing the Si device to produce a metal microneedle matrix,
(4) The fourth method is as follows.
a) Sputtering Ti and Pd on a Si flat plate having a through hole corresponding to a sword mountain type microneedle,
b) Polishing the Si flat plate surface on the wide diameter side of the through hole with the Si flat plate after sputtering, removing the adhered metal, and producing a flat plate in which only the through hole is covered with Ti, Pd.
c) Separately, a UV curing agent is applied to the outer peripheral portion of the non-porous Si flat plate on which Ti and Pd are sputtered (the outer peripheral portion not in contact with the through hole).
d) After irradiating the UV curing agent with UV, a flat plate surface on the side having a small diameter of the through hole is bonded to a non-porous Si plate to produce a Si device.
d) performing metal plating on the Si device, depositing metal from the bottom and side surfaces of the hole of the device, and coating with metal;
e) Dissolving and removing the Si device to produce a metal microneedle matrix,
(5) The fifth method is as follows.
a) Sputtering Ti and Pd on the flat plate surface on the side having a small diameter of the through hole with respect to the Si flat plate having the through hole corresponding to the sword mountain type microneedle,
b) Separately sputtering Ti and Pd on the non-porous Si flat plate surface,
c) Applying PMER to the non-porous Si flat plate after sputtering,
d) With respect to the Si flat plate having a through hole and the non-porous Si flat plate, the sputtered surfaces are bonded so as to face each other with the PMER interposed therebetween.
e) From the surface of the aperture of the Si flat plate, light is irradiated, exposed, and developed to remove the PMER at the tip of the hole to expose the bottom surface of the hole covered with Ti and Pd.
f) Metal plating is performed on the obtained Si device, metal is deposited from the bottom and side surfaces of the hole of the device, and the device is covered with metal.
g) The Si device is dissolved and removed to produce a metal microneedle matrix.
[6] The method for producing a microneedle according to the above [5], wherein the metal is nickel or copper.
[7] The method for producing a microneedle according to the above [5] or [6], wherein PMER is 50 to 70% by weight as a content of propylene glycol monomethyl ether acetate.
[8] The microneedle according to any one of the above [5] to [7], wherein the UV curing agent is a material having a hardness after curing of 96/52 to 100/80 (Shore A / D). Production method.

The production method of the present invention uses a PDMS mold having a through-hole corresponding to a desired Kenzan-type microneedle and uses a temperature range from the transition point to the melting point of the biodegradable resin at a relatively low temperature under a reduced pressure. The transfer process is performed, and the resin is released in the vicinity of the transition point, thereby creating a sword-shaped microneedle made of resin. Due to the characteristics of the manufacturing method and the flexibility of the metal matrix and the PDMS mold based on the matrix, the tip of the microneedle is less likely to be damaged, and the microneedle can be created at a lower temperature. It is a method by which a product with high standard reliability can be manufactured.

Below, the manufacturing method of the Kenyama type | mold microneedle using the biodegradable resin of this invention is demonstrated based on attached drawing below.
The outline of the production method of the present invention is, for example, as shown in FIG. That is, first, metal plating is performed on an Si device having a through-hole (corresponding to a microneedle) manufactured by a semiconductor process to manufacture a metal sword mountain microneedle master. Then, a PDMS mold having a through hole is manufactured by pouring PDMS resin into the metal matrix and forming a flat plate shape. Using the obtained PDMS mold, transfer is performed to a biodegradable resin under reduced pressure to produce a Kenyama microneedle device made of the resin.
As described above, the main features of the manufacturing method of the present invention are a process of manufacturing a Kenyama-type microneedle from a PDMS mold by transfer processing, and a metal microneedle matrix for manufacturing a large number of PDMS molds. Are in two steps.

-First aspect of the present invention-
The first aspect of the present invention relates to a method for manufacturing a Kenyama-type microneedle using a PDMS mold having a through hole.
Microfabrication processes that can be used in making the microneedles disclosed herein include lithography, sputtering, electroplating, and the like. These techniques are described in general books. For example, Taniguchi Satoshi “Nanoimprint Technology for the First Time” (Industry Research Committee, 2005); Elben spokes “Basics of Silicon Micromachining” (Springer Fairlark Tokyo, 2001), Jaeger, Introduction to
Microelectronic Fabrication (Addison-Wesley Publishing Co., Reading)
MA 1988); Runyan, et al., Semiconductor.
Integrated Circuit Processing Technology (Addison-Wesley Publishing Co., Reading)
MA 1990); Proceedings
of the
IEEE Micro
Electro Mechanical
Systems Conference
1987-1998; Rai-Chudhury, Handbook of Microlithography, Micromachining.
& Microfabrication (SSPIE
Optical Engineering
See, Press, Bellingham, WA 1997).
The “biodegradable resin” referred to in the present invention is not particularly limited as long as it is a resin composed of components that are decomposed and absorbed in vivo. Examples of the biodegradable resin include aliphatic polyesters such as polylactic acid, polyglycolic acid, and lactic acid / glycolic acid copolymer, and saccharides such as maltose, lactose, sucrose, mannitol, and sorbitol. Preferably, polylactic acid and polyglycolic acid are suitable as the aliphatic polyester, and maltose is suitable as the polysaccharide. Polylactic acid is, for example, mixed with lactic acid esters such as methyl lactate, butyl lactate, and hexadecyl lactate, or a general heat stabilizer used for stabilizing and modifying plastic resins, a stabilizing aid, The desired physical properties can be obtained by mixing with additives such as plasticizers, antioxidants, light stabilizers, flame retardants, and lubricants.
In the present invention, since a high-temperature transfer process is performed, a biodegradable resin having a melting point or a transition point set to a temperature that can be maintained at a temperature at which the PDMS mold is not softened is desirable.
The “sword mountain type microneedle” referred to in the present invention is a cylindrical or conical, prismatic, or pyramidal microneedle. (1) The width of the base of the microneedle is 50 to 200 μm. 2) The length from the tip of the microneedle to the base is 30 μm to 2 mm, and (3) it has 10 to 500 microneedles constituting the sword mountain shape. Preferably, (1) the width of the base part of the microneedle is 80 to 150 μm, (2) the length from the tip of the microneedle to the base part is 300 μm to 1 mm, and (3) the micrometer constituting the sword mountain shape A needle having 100 to 400 needles can be exemplified.

The term “polydimethylsiloxane (PDMS)” used in the present invention refers to a resin obtained by polymerizing and curing a dimethylsiloxane oligomer with a catalyst or the like. Commercially available PDMS can be used, and preferably, the PDMS resin has a hardness of about 50 Shore A and a tensile strength of about 7 Ppa. For example, Sylgard 184 (Sylgard
184, manufactured by Dow Corning Co., Ltd.), and can be resinized by heat treatment.
The “semiconductor process” referred to in the present invention refers to a means widely used in a semiconductor manufacturing process, and particularly refers to a technique for perforating a silicon flat plate surface. Examples of these means include lithography such as X-ray lithography and photolithography, etching such as ion etching and plasma etching, and drilling with a laser. Preferably, an ICP-RIE (Inductively Coupled Plasma-Reactive Ion Etching) technique capable of deep etching with ions can be used.
The “metal” referred to in the present invention refers to a metal widely used for metal plating, and examples thereof include Ni, NiFe, Au, and Cu. A preferable example is Ni.
The “metal plating” referred to in the present invention can be applied by a general technique in this field. For example, Frazier, et al., “Two Dimensional metallic microarrays for extracellular simulation.
and recording
of neurons "IEEE
Proceeding of the Micro Electro
It can be carried out according to the method described in Mechanical Systems Conference, pages 195-200 (1993).
The term “dissolving and removing Si device” in the present invention refers to removal by a technique of dissolving Si generally used in a semiconductor process. Examples thereof include a 30% calcium hydroxide aqueous solution, an HNO ₃ / HF solution, and SF ₆ plasma.
“Transfer processing” as used in the present invention refers to heating a biodegradable resin, maintaining the temperature of the resin in a temperature range from the transition point to the melting point, and press-bonding it to a mold to form a resin microneedle. . In transferring, the transferred resin is prevented from overflowing from the through hole. If it overflows, delete the overflowing resin part. If transfer is performed at a temperature equal to or higher than the melting point of the resin, the molten resin comes into close contact with the mold, and the frictional resistance at the time of release tends to increase. Therefore, it is desirable that the transfer temperature is lower than the melting point of the resin.
The term “release” as used in the present invention means that the temperature of the pressure-bonded resin is lowered to the vicinity of the transition point, and the resin is removed from the mold before the resin is cured. Since the microneedle mold is a through-hole, unlike a non-through-hole type mold, the microneedle can be easily released. In addition, since the temperature of the mold release is in the vicinity of the transition point, the microneedle is not broken and is easily detached from the mold with some plastic deformation as compared with the case where the resin is solidified. As a result, it is possible to produce a microneedle having a stable quality with few defects at the tip of the microneedle. For example, when polylactic acid is used as a biodegradable resin, the temperature range from the transition point to the melting point is 50 ° C. to 90 ° C. Therefore, the resin is pressure-transferred to the mold in this temperature range, and the resin does not solidify. It is desirable to release the mold around 50 ° C.
The term “under reduced pressure” as used in the present invention is carried out in order to sufficiently fill the through-hole of the mold with the biodegradable resin, and means a reduced pressure at which the object can be achieved. The degree of decompression referred to in the present invention can be adjusted according to the viscosity of the biodegradable resin to be pressure-bonded. For example, when polylactic acid is used as the biodegradable resin, it is pressure-bonded at 65 to 80 ° C. under reduced pressure. It is preferable. In the mold having the through hole of the present invention, unlike the case of the non-through hole, the hole is not blocked by the biodegradable resin, so that the air does not escape and the resin does not sufficiently flow into the mold. In addition, when releasing the transferred resin, there is no air accumulation and, as a result, no negative pressure is generated, so that it is not possible to release the mold or the tip of the needle is broken. .

-Second aspect of the present invention-
The second aspect of the present invention relates to a method for producing a metal microneedle matrix for producing a PDMS mold.
As shown in FIG. 1, a metal microneedle matrix is produced by metal plating using an Si device. There are the following five methods for producing the Si device.
(1) As shown in FIG. 2, a Si flat plate having a through hole and a Si flat plate having no through hole are thermally bonded. In addition, the Si flat plate surface having a narrower diameter of the through hole becomes the bonding surface so that microneedles can be formed. A Si device is fabricated by sputtering Ti and Pd on the device after thermal bonding.
(2) As shown in FIG. 3, Ti and Pd are sputtered onto a Si flat plate having no through-hole to produce a Si flat plate coated with Ti and Pd. A Si flat plate having a through hole is superimposed on the Si flat plate and fixed with a protective tape. In this manner, a device in which the bottom surface of the hole of the Si device is coated with a metal is manufactured.
(3) As shown in FIG. 4, Ti and Pd are sputtered onto a Si flat plate having no through-holes to produce a Si flat plate covered with Ti and Pd. A UV curing agent is applied to the outer periphery of the Si flat plate. After irradiating the UV curing agent with UV, the Si flat plate with through holes and the Si flat plate without through holes are pressure-bonded and fixed so that the Si flat plate surface with a narrower diameter of the through hole becomes the bonding surface. In this manner, a device in which the bottom surface of the hole of the Si device is coated with a metal is manufactured.
(4) As shown in FIG. 5, Ti and Pd are sputtered onto a Si flat plate having no through-holes to produce a Si flat plate covered with Ti and Pd. Ti and Pd are sputtered on the surface of the Si flat plate with through holes having a large diameter to cover the through holes with Ti and Pd. A UV curing agent is applied to the outer periphery of a Si flat plate coated with Ti and Pd and having no through holes. After irradiating the UV curing agent with UV, the Si flat plate with through holes and the Si flat plate without through holes are pressure-bonded and fixed so that the Si flat plate surface with a narrower diameter of the through hole becomes the bonding surface. Thus, a device in which the bottom and side surfaces of the hole of the Si device are coated with metal is manufactured.
(5) As shown in FIG. 6, Ti and Pd are sputtered onto a Si flat plate having no through-holes to produce a Si flat plate coated with Ti and Pd. Furthermore, the Ti · Pd coating surface of the Si flat plate is coated with PMER. Ti and Pd are sputtered on the surface of the Si flat plate with through holes having a small diameter to cover the through holes and the flat plate surface with Ti and Pd. The Si flat plate with the through hole and the Si flat plate coated with PMER (Tokyo Ohka Photopolymer) are bonded and fixed so that the surface with the small diameter of the Si flat plate with the through hole becomes the bonding surface. The exposed PMER is removed by irradiating and developing light from the opening of the Si device. Thereby, a device in which the bottom and side surfaces of the hole of the Si device are coated with metal is manufactured. Note that the bottom and side surfaces are separated via a PMER.

The above five methods have the following characteristics in order to efficiently perform metal plating.
Feature (1): According to the thermal bonding, silicon is strongly bonded to each other, so that the plating solution does not enter between the substrates and there is no fear of peeling between the substrates.
Feature (2): The substrates can be easily and simply attached without applying pressure or heating as in thermal bonding. Since (1) is plated from the surface side, the bottom may be insufficiently plated. However, in (2), since it is plated from the bottom surface, formation of the entire shape can be reliably expected at the time of plating.
Feature (3): Although it takes a little more labor than a tape, it can be bonded more easily and reliably than a thermal bonding without any gaps between substrates. What can be done from the bottom has the same merit as (2).
(4) Features: (2) and (3) are plated only from the bottom, but (4) can be plated from the side of the hole as well as the bottom. Thereby, shape plating can be expected more reliably.
(5) Feature: Similar to (4), there is an advantage that plating can be performed from both the bottom and side surfaces. However, since PMER is used as a fixing method, the substrates can be bonded more reliably and the reliability can be increased.

In the present invention, the definitions of the terms in the first aspect are the same unless otherwise specified.
The term “thermal bonding” as used in the present invention refers to a technique for bonding silicon by heating a silicon substrate and applying pressure thereto. The bonding temperature can be in the range of 900 ° C to 1000 ° C.
The “UV curing agent” referred to in the present invention is composed of an oligomer, a monomer, and a photoinitiator, and examples thereof include acrylic acid-based monomers. Preferable examples include those having a hardness after curing of 96/52 to 100/80 Shore A / D. More preferable examples include GL-4001 (manufactured by Glue Lab Co., Ltd.) or GLX39-79 (manufactured by Glue Lab Co., Ltd.).
“PMER” as used in the present invention means a photoresist, and preferably contains 50 to 70% by weight of propylene glycol monoacetate. More preferably, P-HM3000PM (made by Tokyo Ohka) or P-LA900PM (made by Tokyo Ohka) can be mentioned.

  The present invention will be specifically described below with reference to examples. However, the present invention is not limited to the following examples.

(Example 1) Production of Si flat plate having through-holes A photosensitive resist was coated on a Si flat plate (4 inch diameter) having a thickness of 500 µm by spin coating. A microneedle pattern (a pattern in which 400 holes having a diameter of 100 μm are arranged) was drawn by UV exposure. Development is performed by a dipping method, and an opening corresponding to the size of the microneedle is opened. A drawing pattern is transferred onto a Si flat plate by an inductively coupled plasma reactive ion etching (ICP-RIE) method using SF6 gas to obtain a through hole. The remaining photosensitive resist was removed by an RIE method using O ₂ gas to obtain a Si flat plate having a through hole.

(Example 2) Manufacturing method of Si device for producing a metal mold for a microneedle (1) Thermal bonding type:
The Si flat plate having the through hole obtained in Example 1 and the non-porous Si flat plate of the same size are overlapped so that a Si plane having a large aperture diameter remains. This device is heated at about 1000 ° C. in an oxidation furnace for 30 minutes to perform thermal bonding of the Si flat plate.
(2) Protective tape fixed type (metal bottom covering the mold hole):
Similar to the above (1), the Si flat plates are overlapped. Secure both Si plates with protective tape.
(3) UV curing agent adhesion type (metal bottom covering the mold hole):
The Si flat plate having through holes obtained in Example 1 and the non-porous Si flat plate having the same size and sputtered with Ti and Pd are overlapped. At this time, GL-4001 is applied around the Si flat plate, UV irradiation is performed, and both Si flat plates are overlapped. By fixing as it is, a through hole in which the bottom surface of the mold hole is coated with metal is obtained.
(4) UV adhesive mold (metal bottom and side surfaces of mold hole):
The Si flat plate having through-holes obtained in Example 1 is subjected to sputtering with Ti and Pd from the wider opening, and the surface of Ti and Pd on the Si flat plate is removed by polishing. Thus, a Si flat plate in which only the through holes obtained in this way are coated with Ti and Pd is obtained.
Using the Si flat plate and a non-porous Si flat plate sputtered with Ti and Pd of the same size, bonding is performed in the same manner as in (3) above, and the bottom and side surfaces of the mold hole are made of Ti and Pd. A coated Si device is obtained.
(5) PMER adhesion type (metal bottom covers and side surfaces of mold holes):
The Si flat plate having a through hole obtained in Example 1 is subjected to sputtering with Ti and Pd from the narrower opening. Further, sputtering is performed with Ti and Pd on a non-porous Si flat plate, and PMER resin (P-HM3000PM) is applied on the Ti and Pd coating. On top of this, a Si flat plate having a through hole is overlaid on the narrower side of the opening. UV is irradiated from the opening of the Si device and developed. The photosensitive portion is removed to obtain a Si device in which the bottom and side surfaces of the mold hole are covered with Ti and Pd.

(Example 3) Production of metal mold for microneedle Using the Si device obtained in (3) of Example 2, a pH 4.5 nickel plating aqueous solution (nickel sulfamate, boric acid, sodium lauryl sulfate) was used. Immerse and plate at 50 ° C. for 20 hours.
The plated Si device was wet etched with an HNO ₃ / HF solution to remove only the Si device. As a result, a nickel needle mold of microneedles could be produced.

(Example 4) Production of PDMS microneedle mold Using the nickel matrix obtained in Example 3, PDMS (SILPOT 184W / C) and a polymerization catalyst were mixed at a ratio of 10: 1. The mixture is poured onto a flat plate until the microneedles are finally hidden. The temperature is set at 70 ° C. for 30 minutes to cure the PDMS. After cooling, the microneedle mold made of PDMS could be produced by releasing from the nickel matrix.

(Example 5) Production of biodegradable resin microneedles Using the PDMS mold obtained in Example 4, the polylactic acid resin was heated to around 85 ° C and pressure-bonded under a negative pressure of-. When the temperature of the polylactic acid resin is lowered to around 50 ° C., the mold and the polylactic acid resin are released from the mold. Unnecessary burrs of the released polylactic acid resin were cut to obtain polylactic acid resin microneedles shown in FIGS.

According to the microneedle manufacturing method of the present invention, for example, as shown in FIG. 1, a PDMS mold having a through-hole can be produced in large quantities by using a metal master mold, and a good quality sword-shaped microneedle device. Can be mass-produced. In particular, the method for producing a metal mold for a microneedle according to the present invention can produce a metal mold with high accuracy, so that PDMS molds of good quality can be produced in large quantities.

Schematic of manufacturing method of Kenyama type resin microneedle device Thermal bonding type Si device Si device with fixed protective tape UV curing agent adhesion type Si device UV curing agent adhesion type Si device having through-holes sputtered with Ti and Pd PMER fixed Si device Micro needle made of polylactic acid resin of the present invention (overall view) Micro needle made of polylactic acid resin of the present invention (enlarged view)

Claims (8)

A method for producing a Kenyama microneedle made of biodegradable resin having the following shape,
(1) In order to fabricate the resin-made Kenzan-type microneedles, a polydimethylsiloxane (PDMS) mold having through holes (cylinders, cones, prisms, pyramids) matching the size of the microneedles is used as follows. To make,
a) 10 to 500 cylindrical, prismatic, conical or pyramidal holes having a size of about 50 to 200 μm in a silicon (Si) flat plate having a thickness corresponding to the length of a microneedle. Open,
b) Metal plating is performed on the Si device manufactured as described above, and the through hole and the surface of the device are covered and filled with metal.
c) Dissolving and removing the Si device to produce a metal needle mold of microneedles.
d) Apply and solidify PDMS resin in the form of a flat plate on the metal matrix to create a PDMS mold having through holes of the same type as the Si device.
(2) High-temperature transfer processing is performed on the biodegradable resin under reduced pressure using the PDMS mold.
(3) The temperature of the resin is cooled to near the transition point, and the resin is released from the mold.
A method for producing a Kenyama-type microneedle made of a biodegradable resin.   The method of manufacturing a microneedle according to claim 1, wherein the metal plating is nickel plating or copper plating.   The method for producing a microneedle according to claim 1 or 2, wherein the biodegradable resin is polylactic acid. The Kenyama type microneedle (1) The width of the base of the microneedle is 50 to 200 μm
(2) The length from the tip of the microneedle to the base is 30 μ to 2 mm
(3) The method for producing microneedles according to any one of claims 1 to 3, wherein the number is 10 to 500. A method for manufacturing a metal microneedle mold, using a Si flat plate having a thickness corresponding to the length of a microneedle, and a cylindrical, prismatic, or conical shape having a size of about 50 to 200 μm in a semiconductor process. Alternatively, a method for producing a metal mother die comprising opening 10 to 500 pyramidal through holes and then selecting one of the following five methods:

(1) The first method is as follows:
a) A Si flat plate having a through hole corresponding to a sword-shaped microneedle is thermally bonded to a non-porous Si flat plate on a plane having a smaller diameter of the through hole.
b) Sputtering or vacuum-depositing a base metal on the surface of the opening of the Si device obtained by thermal bonding,
c) Metal plating is performed on the Si device coated with the base metal, and the metal is coated and filled.
d) Dissolving and removing the Si device to obtain a metal microneedle matrix,

(2) The second method is as follows:
a) The Si flat plate having a through hole corresponding to the sword-shaped microneedle is combined with a non-porous Si flat plate to which Ti and Pd are adhered on a plane having a smaller diameter of the through hole.
b) Fixing the two Si flat plates so as not to be separated by a protective tape, and producing a Si device.
c) performing metal plating on the fixed Si mold, depositing metal from the bottom of the mold, and covering and filling the device with metal;
d) Dissolving and removing the Si device to obtain a metal microneedle matrix,

(3) The third method is as follows.
a) A UV curing agent is applied to the outer peripheral portion of a non-porous Si flat plate obtained by sputtering Ti and Pd, and UV is irradiated.
b) A Si flat plate having a through-hole corresponding to the sword-shaped microneedle and the non-porous Si flat plate are bonded together on a plane having a smaller diameter of the through-hole to produce a Si device.
c) Metal plating is performed on the hole surface of the Si device, metal is deposited from the bottom of the hole, and the surface of the device hole is covered with metal.
d) dissolving and removing the Si device to produce a metal microneedle matrix,

(4) The fourth method is as follows.
a) Sputtering Ti and Pd on a Si flat plate having a through hole corresponding to a sword mountain type microneedle,
b) Polishing the Si flat plate surface on the wide diameter side of the through hole with the Si flat plate after sputtering, and removing the adhered metal to produce a flat plate in which only the through hole is covered with Ti and Pd.
c) Separately, a UV curing agent is applied to the outer peripheral portion of the non-porous Si flat plate on which Ti and Pd are sputtered (the outer peripheral portion not in contact with the through hole).
d) After irradiating the UV curing agent with UV, a flat plate surface on the side having a small diameter of the through hole is bonded to a non-porous Si plate to produce a Si device.
d) performing metal plating on the Si device, depositing metal from the bottom and side surfaces of the hole of the device, and coating with metal;
e) Dissolving and removing the Si device to produce a metal microneedle matrix,

(5) The fifth method is as follows.
a) Sputtering Ti and Pd on the flat plate surface on the side having a small diameter of the through hole with respect to the Si flat plate having the through hole corresponding to the sword mountain type microneedle,
b) Separately sputtering Ti and Pd on the non-porous Si flat plate surface,
c) Applying PMER to the non-porous Si flat plate after sputtering,
d) With respect to the Si flat plate having a through hole and the non-porous Si flat plate, the sputtered surfaces are bonded so as to face each other with the PMER interposed therebetween.
e) From the surface of the aperture of the Si flat plate, light is irradiated, exposed, and developed to remove the PMER at the tip of the hole to expose the bottom surface of the hole covered with Ti and Pd.
f) Metal plating is performed on the obtained Si device, metal is deposited from the bottom and side surfaces of the hole of the device, and the device is covered with metal.
g) The Si device is dissolved and removed to produce a metal microneedle matrix.
The manufacturing method of the micro needle | hook of Claim 5 whose metal is nickel or copper.
  The manufacturing method of the microneedle of Claim 5 or 6 whose PMER is 50 to 70 weight% as a content of propylene glycol monomethyl ether acetate. The manufacturing method of the microneedle in any one of Claims 5-7 whose UV hardening | curing agent is a material of the range of 96 / 52-100 / 80 (Shore A / D) as the hardness after hardening.