JP5223278B2 - Microneedle manufacturing method - Google Patents

Description

  The present invention relates to a method for manufacturing a microneedle.

  A percutaneous absorption method is known as a method of infiltrating a drug from the skin and administering the drug into the body. In this method, a liquid or gel-like drug is applied to the surface of a living body such as skin or mucous membrane. This method is non-invasive and allows a drug to be easily administered without causing pain to the human body. However, when the molecular weight of the target drug is large or it is a water-soluble drug, it is hardly absorbed into the body even when applied to the surface of a living body, and it is difficult to transdermally administer these drugs.

  Therefore, in order to efficiently absorb these drugs into the body, a method of perforating the skin using microneedles having many needles on the order of μm and directly administering the drug into the skin has attracted attention. According to this method, a drug can be easily administered subcutaneously without using a special device for medication. (For example, see Patent Document 1)

  The shape of the microneedle used at this time is required to have a sufficient fineness and tip angle for piercing the skin, and a sufficient length for allowing the drug solution to penetrate subcutaneously. In order to suppress pain, it is desirable to penetrate the stratum corneum, which is the outermost layer of the skin, and not reach the nerve layer. The diameter of the needle is from several μm to 100 μm, and the length of the needle is from several tens of μm. It is desirable to be several hundred μm.

  The material constituting the microneedle is required not to adversely affect the human body even if the microneedle is broken and remains in the body. As such materials, medical silicone resins, and biocompatible resins such as maltose, polylactic acid, and dextran are promising. (For example, see Patent Document 2)

  In order to manufacture such a fine structure at low cost and in large quantities, a transfer molding method represented by an injection molding method, an imprinting method, a casting method and the like is effective. However, in any method, in order to perform molding, a mold in which a desired shape is inverted is necessary, and the aspect ratio (height or depth ratio to the diameter of the structure) is similar to that of a microneedle. It is necessary to form a structure that is high and requires sharpening of the tip.

  For example, as a method for manufacturing the above-described microneedle, a manufacturing method has been proposed in which a microneedle original plate is manufactured by X-ray lithography, a replica plate is formed from the original plate, and transfer molding is performed (see, for example, Patent Document 3). .

For example, a manufacturing method has been proposed in which a microneedle master is manufactured by machining, a replica is made from the master, and transfer molding is performed (see, for example, Patent Document 4).
US Pat. No. 6,183,434 JP-A-2005-21677 JP 2005-246595 A JP-T-2006-513811

  In some microneedles, a shape having a hole in the center of the microneedle is desirable instead of a simple protrusion shape (for example, a microneedle used for a device configured to collect / supply body fluid / medical solution through the hole).

  Then, an object of this invention is to provide the microneedle manufacturing method suitable for manufacture of the microneedle of the shape which provided the hole in the center.

The present invention according to claim 1 is a step of providing a hole in a substrate, a step of filling the hole with a filler, a portion of the filler exposed from the substrate, and a thickness of the exposed portion in the thickness direction of the substrate. A step of deforming to have a distribution, and a step of performing anisotropic etching in the substrate thickness direction on the substrate using the deformed filler as a mask, and etching the substrate while erasing the thin portion of the filler Removing the filler and producing microneedles, using the produced microneedles as a mother mold, producing a replica from the master, and performing transfer molding using the replica And a step of manufacturing a needle.

  The present invention described in claim 2 is the microneedle manufacturing method according to claim 1, wherein the filler is made of a thermoplastic resin.

  The present invention described in claim 3 is the microneedle manufacturing method according to claim 1 or 2, wherein the hole is a through hole.

  The present invention described in claim 4 is the microneedle manufacturing method according to claim 1 or 2, wherein the hole is a non-through hole.

The present invention according to claim 5 is the microneedle manufacturing method according to any one of claims 1 to 4, wherein the step of deforming the filler is performed by thermal reflow. It is a manufacturing method.

The microneedle manufacturing method of the present invention is characterized in that a hole is provided in a substrate, a filler is filled in the hole, a part of the filler is deformed, and the substrate is etched.
According to the configuration of the present invention, since the substrate is etched using a part of the filler as a mask, the position of the microneedle protrusion and the position of the hole correspond one-on-one. Thus, the microneedle shape provided with the hole can be formed.
Therefore, a microneedle having a shape with a hole in the center can be preferably manufactured.
In particular, in the case of microneedles in which a plurality of needles are arranged, the position of the protrusion and the position of the hole are aligned in a self-aligned manner for each microneedle, so there is no one-to-one correspondence. To do. For this reason, in the case of a microneedle in which a plurality of needles are arranged, the effect of the microneedle manufacturing method of the present invention is very large.

  Hereinafter, the microneedle manufacturing method of the present invention will be described.

<Step of providing holes in the substrate>
First, holes are provided in the substrate.

  The substrate is preferably a material with processing characteristics suitable for forming the holes. For example, a silicon substrate, a metal material such as aluminum or stainless steel, or a synthetic resin such as polycarbonate, polystyrene, acrylic resin, or fluorine resin may be used.

  As a method for providing the holes, any method may be used as long as it can form a single or a plurality of holes having a desired opening diameter and depth with respect to the substrate. For example, you may form by various machine processing, laser processing, reactive ion etching, focused ion beam processing, etc.

  Further, when it is necessary to form a plurality of needles, holes are provided in accordance with the arrangement and pitch interval of the needles to be formed.

  Moreover, it is preferable that a hole is a through-hole. By being a through-hole, body fluid / medical solution can be collected / supplied through the through-hole. For this reason, it can be suitably used for a body fluid collection / drug delivery device having a constitution in which a chemical solution supply means and a body fluid collection means are provided on the side opposite to the side on which the projections of the microneedle are formed.

  Moreover, it is preferable that a hole is a non-through-hole. By being a non-through hole, body fluid / chemical solution can be retained inside the non-through hole. For this reason, it can use suitably for the device of the structure which apply | coats a chemical | medical solution to the side in which the processus | protrusion of the microneedle was formed, and the device which test | inspects a bodily fluid after pressing on the skin.

<Step of filling the hole with a filler>
Next, the formed holes are filled with a filler.

  Any filler can be used as long as it can be filled in a hole of several μm to several hundred μm. For example, a metal material such as Ni, silicone, a resin material, or the like may be used.

  As a method for filling the filler, a known method may be used as appropriate according to the selected filler. For example, the filling may be performed by a plating method such as electrolytic plating, a method of melting a material and filling the hole.

  The filler is preferably a thermoplastic resin. By using a thermoplastic resin, deformation can be performed using thermal reflow in a <step of deforming the filler so as to have a thickness distribution in the substrate thickness direction> described later.

<Process of transforming the filler to have a thickness distribution in the substrate thickness direction>
Next, a part of the filler is exposed from the substrate, and the exposed portion is deformed so as to have a thickness distribution in the substrate thickness direction.

  A method for exposing a part of the filler from the substrate may be appropriately selected according to the selected substrate, the selected filler, and the desired microneedle shape. For example, wet etching using chemicals, dry etching using gas, plasma, reactive ions, or the like, or fine machining may be used.

  At this time, the height of the exposed filler from the substrate surface may be appropriately determined according to the desired height of the microneedle. The height of the microneedles to be manufactured can be controlled by the etching selectivity between the substrate and the filler and the height of the exposed filler from the substrate surface. For example, when a silicon substrate and a general thermoplastic resin are used, the height of the exposed filler from the substrate surface is several μm to several hundred μm in order to obtain a microneedle of several tens μm to several hundred μm. It should be a degree.

  The method of deforming the exposed portion so as to have a thickness distribution in the substrate thickness direction may be appropriately selected according to the selected filler. For example, when a thermoplastic resin is used as the filler, the deformation may be performed by thermal reflow. When the filler is fluidized by thermal reflow, the filler is deformed so as to have a thickness distribution in the substrate thickness direction according to the surface tension of the fluidized filler. At this time, by controlling the heating temperature and heating time of the heat treatment, it is possible to control the width of the deformed portion and the degree of shape change in the filler.

<Process for etching the substrate>
Next, the substrate is etched using the deformed filler as a mask.
By anisotropically etching in the vertical direction using the deformed filler as a mask, it gradually disappears from the thin part of the filler, and the substrate with a high etching rate is etched into a tapered shape. The At this time, the mask is gradually removed, and the microneedle is formed by finally removing the mask after it has converged to a minute range, so that contamination due to dropping off of the etching mask does not occur. In addition, a microneedle having a sharp tip shape can be manufactured.

  Any etching method may be used as long as the selected substrate and the selected filler have a higher substrate etching rate and can perform anisotropic etching in the vertical direction. For example, when silicon is used as the substrate, reactive ion etching using a fluorine-based gas may be used.

  Further, the tip angle of the microneedle can be controlled by the etching selectivity of the filler and the substrate (ratio of the etching rate of the substrate to the etching rate of the filler). When the etching selectivity is high, the tip angle of the microneedle is sharp and the height tends to be high. When the etching selectivity is low, the tip angle becomes dull and the height tends to be low.

<Process for removing filler>
Next, the filler is removed. As a method for removing the filler, a method suitable for the selected filler may be used. For example, when a general thermoplastic resin is used, wet processing using an organic solvent or a mixed solution of sulfuric acid and hydrogen peroxide, dry processing using oxygen plasma, or the like may be performed.

From the above, a microneedle having a shape with a hole in the center can be manufactured.
When a microneedle having a through hole is desired, a step of exposing the hole by providing a non-through hole, performing the above process, and polishing from the side opposite to the side on which the protrusion is formed may be performed. . At this time, the step of exposing the holes and the step of removing the filler may be performed in a row.

Furthermore, it is preferable that the manufacturing method further includes a step of using the manufactured microneedle as a mother die, producing a duplicate plate from the mother die, and a step of performing transfer molding using the duplicate plate. By producing a replica plate with high mechanical strength that is integrally molded, a large amount of needle-like bodies can be manufactured with the same replica plate, which makes it possible to reduce production costs and increase productivity. . In addition, since the transfer material can be selected without considering the processing characteristics for microfabrication, in particular, a needle-like body made of a biocompatible material can be suitably manufactured.
As the transfer molding, for example, an imprint method, a hot embossing method, an injection molding method, a casting method, or the like may be used.
As the transfer material, for example, a medical silicone resin that is a biocompatible material, maltose, polylactic acid, dextran, chitin chitosan, or the like may be used.

  In addition, when a microneedle having a through hole is desired, after performing transfer molding, a step of polishing from the side opposite to the side on which the protrusion is formed and exposing the hole may be performed. By exposing the hole, a microneedle having a through hole can be obtained.

<Example 1>
In this embodiment, an example of manufacturing a silicon microneedle having a hole in the center is shown.

  First, a silicon wafer was prepared as a substrate. The crystal plane orientation of this silicon wafer was (100) and the thickness was 525 μm (FIG. 1 (a)).

  Next, a positive resist (PMER P-LA900, manufactured by Tokyo Ohka Kogyo Co., Ltd.) was coated to a thickness of 10 μm as an etching mask on the silicon wafer, and a resist pattern having a square opening with a side of 20 μm was formed by photolithography (FIG. 1 (b)).

  Next, using a resist pattern as an etching mask, square holes with a depth of 400 μm are formed by ICP (Inductively Coupled Plasma) etching using a fluorine-based gas, and the remaining resist and reaction residues are organically removed. Removal was performed using a solvent, an acid solution, and an alkali solution, and the silicon wafer was cleaned (FIG. 1C).

Next, a PMMA (poly (methyl methacrylate)) solution, which is a thermoplastic resin, was deposited on the surface of the silicon wafer in which the holes were formed, and then the temperature was raised to about 110 ° C. to cause the solution to flow (casting) ( FIG. 1 (d)).
At this time, in order to prevent air from remaining in the hole, an operation was performed using a vacuum chamber.

  Next, after the PMMA was completely solidified, it was mechanically polished until the silicon wafer surface was exposed (FIG. 1 (e)).

  Next, the surface of the silicon wafer was selectively etched by 40 μm by plasma etching using a fluorine-based gas, and a part of the PMMA buried in the hole portion was projected (FIG. 1F).

  Next, the silicon wafer is put into a clean oven set at about 150 ° C. and heat-treated for about 30 minutes, so that the PMMA protrudes from the substrate to reflow, has a thickness distribution, and expands to about 100 μm. Deformed (FIG. 1 (g)).

Next, etching with a depth of 300 μm was performed by ICP etching using a fluorine-based gas using PMMA having a thickness distribution as a mask (FIG. 1H).
Since the portion where PMMA protrudes from the substrate has a thickness distribution, as a result of being gradually etched from the outer thin portion, the shape of the silicon wafer after etching became a tapered shape, and a microneedle shape was formed.

Next, for the purpose of removing the residue after etching and removing PMMA embedded in the central hole, the silicon wafer was cleaned using an organic solvent or a sulfuric acid / hydrogen peroxide mixture (FIG. 1 (i)). )).
From the above, a microneedle having a hole in the center could be manufactured.

<Example 2>
A microneedle was produced in the same manner as in Example 1. However, before removing the PMMA embedded in the central hole, polishing was performed from the side opposite to the side on which the protrusions were formed to expose the filler on the back surface.
From the above, a microneedle having a through hole could be manufactured (FIG. 1 (j)).

<Example 3>
In this example, a method for producing maltose, dextran, chitin chitosan, polylactic acid microneedles having a through-hole in the center using the silicon microneedles obtained in Example 1 as an original plate is shown.

  First, in the procedure of Example 1, a silicon microneedle structure having a hole with a depth of 400 μm and an opening width of 20 μm and a height of 300 μm was formed at the center (FIG. 2A).

  Next, after forming a very thin nickel layer by electroless plating on a silicon wafer on which microneedles were formed, nickel was formed to a thickness of 1 mm by electrolytic plating using this nickel layer as a seed layer (FIG. 2). (B)).

  Next, silicon was dissolved using an aqueous potassium hydroxide solution having a concentration of 25% and a liquid temperature of 90 ° C. to produce a duplicated plate according to the present invention made of nickel (FIG. 2C).

  Next, maltose, dextran, chitin chitosan, and polylactic acid were filled in the duplicate plate by a casting method using the duplicate plate (FIG. 2 (d)).

Next, the duplicate plate was physically peeled from the transfer material. It was confirmed that a needle having a height of about 300 μm was formed with any material, similar to the silicon original plate (FIG. 2E).
From the above, a microneedle having a hole in the center could be manufactured.

<Example 4>
A microneedle was produced in the same manner as in Example 3.
Next, it grind | polished from the opposite side to the side in which the protrusion was formed, and the hole was exposed on the back surface (FIG. 2 (f)).
From the above, a microneedle having a through hole could be manufactured.

It is process schematic which shows an example of the microneedle manufacturing method of this invention. It is process schematic which shows an example of the microneedle manufacturing method of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 101 ... Substrate 102 ... Etching mask 103 ... Hole 104 ... Filler 105 ... Filler 106 embedded in the hole 106 ... Filler having island-shaped tip with thickness distribution 107 ... Microneedle 108 with a non-through hole in the center ... Microneedle 201 with a through hole in the center ... Microneedle original plate 202 with a hole in the center ... Metal layer 203 formed by plating・ Replica plate 204... Resin 205 embedded in replica plate... Microneedle 206 having a non-through hole in the center... Microneedle having a through hole in the center

Claims (5)

Providing a hole in the substrate;
Filling the pores with a filler;
A step of exposing a part of the filler from the substrate and deforming the exposed portion to have a thickness distribution in the substrate thickness direction;
Using the deformed filler as a mask, performing anisotropic etching on the substrate in the substrate thickness direction, and etching the substrate while erasing the thin portion of the filler ,
Removing the filler and producing microneedles ;
Using the manufactured microneedle as a matrix, and producing a replica from the matrix;
A step of producing a microneedle by performing transfer molding using the duplicate plate;
A microneedle manufacturing method comprising: The microneedle manufacturing method according to claim 1,
The method for producing a microneedle, wherein the filler is made of a thermoplastic resin. It is a microneedle manufacturing method in any one of Claim 1 or 2,
The microneedle manufacturing method, wherein the hole is a through hole. It is a microneedle manufacturing method in any one of Claim 1 or 2,
The microneedle manufacturing method, wherein the hole is a non-through hole. A microneedle manufacturing method according to any one of claims 1 to 4,
The step of deforming the filler is performed by thermal reflow.
A method for producing microneedles.

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