JP4940975B2 - Manufacturing method of needle-shaped body - Google Patents

Description

  The present invention relates to a fine needle-like body.

  The percutaneous absorption method, which is a method of infiltrating a drug from the skin and administering the drug into the body, is used as a method that can be easily administered without causing pain to the human body. There are drugs that are difficult to administer by transdermal absorption. As a method for efficiently absorbing these drugs into the body, a method of perforating the skin using a fine needle (microneedle) on the order of μm and directly administering the drug into the skin has attracted attention. According to this method, it is possible to easily administer a drug subcutaneously without using a special medication device (see Patent Document 1).

  The shape of the fine needle-like body 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, The diameter of the needle is several μm to several hundred μm, and the length of the needle penetrates the stratum corneum, which is the outermost layer of the skin, and does not reach the nerve layer, specifically several tens μm to several hundred μm, The tip angle of the needle is preferably an acute angle, specifically, 30 ° or less.

  More specifically, it is required to penetrate the stratum corneum that is the outermost skin layer. The thickness of the stratum corneum varies slightly depending on the part of the human body, but is about 20 μm on average. In addition, an epidermis having a thickness of about 200 μm to 350 μm exists under the stratum corneum, and further, a dermis layer in which capillaries are stretched exists under the epidermis. For this reason, in order to penetrate the stratum corneum and allow the chemical solution to penetrate, a needle of at least 20 μm or more is required. Further, when producing a needle-like body for the purpose of blood collection, a needle-like body having a height of at least 350 μm or more is required due to the above-described skin structure.

  In addition, the material constituting the needle-shaped body must be a material that does not adversely affect the human body even if the damaged needle-shaped body tip remains in the body. Biocompatible resins such as resins and maltose, polylactic acid, dextran, etc. are considered promising (see Patent Document 2).

  In order to surely penetrate the stratum corneum, it is desired that the needle has a high puncture ability. However, if the needle tip angle is sharpened in order to improve the needle puncturing capability, the mechanical strength of the needle tip decreases and the needle tip breaks or deforms when it is pressed against the skin. It becomes easy to do. For this reason, there is a variation in the degree of penetration of the microneedles into the skin, and as a result, there is a problem that it is difficult to obtain stable drug administration or pharmacological effects.

  As a method for suppressing such breakage of the tip of the needle-like body, a method of increasing the mechanical strength by making the shape of the tip of the needle-like body flat is known (see Patent Document 3).

On the other hand, a free-form surface is designed as a design of a curved surface in which a shape existing in nature, a shape obtained by experiments, etc. is reproduced on a computer, or a curved surface in a building or industrial product. A free-form surface is a curved surface defined by combining curves that can be expressed by a function, and it is known that the shape can be designed using a three-dimensional CAD drawing device or the like (see Patent Document 4).
US Pat. No. 6,183,434 Japanese Patent Laid-Open No. 2005-21677 JP 2005-533625 A Japanese Patent Laid-Open No. 06-139315

  However, when the shape of the tip of the needle-like body is a flat part, the load generated when the needle is pressed against the skin is dispersed, so that the puncture ability is significantly reduced. In addition, the puncture ability is reduced, so that the skin is deformed without being able to penetrate the skin at the time of pressing, and it receives physical repulsion from the pushed-back skin, so that the needle-like body is not the tip of the needle-like body. There is a risk of damage or deformation from the side.

  In particular, when a plurality of needles are regularly arranged (for example, the needles are arranged in an array), the puncture ability is significantly reduced due to pressure dispersion, which may lead to a decrease in drug administration effect and reproducibility.

  Accordingly, the present invention has been made to solve the above-described problems, and provides a needle-like body that has sufficient puncture ability and can suppress breakage of the needle-like body during puncture. For the purpose.

The present invention according to claim 1 is a method of manufacturing a fine needle-like body, wherein a step of applying a resist to a substrate, a step of patterning the resist to form a resist pattern, and a step of applying a resist to the substrate Etching from a direction, and comprising a step of forming an etched substrate and a needle-like body having a curved shape on the etched substrate and having a tip made of a resist. is there.
In this specification, the term “needle” is defined to include not only a single needle but also a structure in which a plurality of needles are regularly arranged (for example, arranged in an array). .

The present invention is defined in claim 2, the curved surface of the front Kiharijotai tip bicubic curved, Coons curved surface, Bezier surface, B- spline surface, free selected from NURBS curved surface, the group consisting of Gregory curved surfaces It is a curved surface, The method for producing a needle-like body according to claim 1 .
In this specification, “free-form surface” is defined as a curved surface defined by combining curves that can be expressed by functions.

The present invention as set forth in claim 3, wherein etching is performed from the direction in which a resist is applied to the substrate, and the etched substrate and a needle-like body having a curved surface on the etched substrate and having a tip portion made of resist, In the process, the base of the needle-like body is the origin, the axial direction from the base to the tip of the needle-like body is the Z-axis, an arbitrary axial direction perpendicular to the Z-axis is the X-axis, In a three-dimensional coordinate system in which the axis direction perpendicular to both the X axis is the Y axis, the needle side surface portion has a tapered shape and the needle side surface portion has a taper angle of 30 ° or less. 3. The method for manufacturing a needle-shaped body according to claim 1 , wherein the etching is stopped within a range where the coordinates on the curved surface of the distal end of the body satisfy the following mathematical formula .
In the present specification, the “base of the needle-like body” means the surface of the substrate obtained by moving the contact point where the surface parallel to the substrate surface and the curved surface of the tip of the needle-like body contact at one point perpendicularly to the substrate direction. Defined as one point above.

According to the present invention of claim 4, the resist pattern formed in the step of patterning the resist is a cylindrical resist pattern, and the cylindrical resist pattern is cross-sectionally viewed from the side before the etching step. The method for manufacturing a needle-like body according to any one of claims 1 to 3, further comprising a step of deforming the projected image into a semicircular shape .

The present invention according to claim 5 is characterized in that the step of deforming the cylindrical resist pattern so that a cross-sectional projection image from the side surface has a semicircular shape is performed by heat. It is a manufacturing method of an acicular body .

According to a sixth aspect of the present invention, the needle-shaped body manufactured by the method for manufacturing a needle-shaped body according to any one of the first to fifth aspects is used as a matrix, a duplicate plate is formed, and transfer processing is performed. This is a method for producing a needle-like body.

  The needle-like body of the present invention improves the mechanical strength of the tip of the needle-like body by concentrating the tip of the needle-like body and concentrates the load generated when the needle is pressed on the tip of the needle-like body. It can be made. For this reason, it becomes possible to suppress the breakage of the needle-like body without lowering the puncture ability.

Hereinafter, the acicular body of the present invention will be described.
The needle-shaped body of the present invention is
A needle-like body provided on a substrate,
The tip of the needle-like body is a curved surface.

  The needle-like body of the present invention improves the mechanical strength of the tip of the needle-like body by concentrating the tip of the needle-like body and concentrates the load generated when the needle is pressed on the tip of the needle-like body. It can be made. For this reason, it becomes possible to suppress the breakage of the needle-like body without lowering the puncture ability.

  The curved surface shape of the tip of the needle-like body is preferably a free curved surface (for example, a bicubic curved surface, a Coons curved surface, a Bezier curved surface, a B-spline curved surface, a Nervous curved surface, a Gregory curved surface). By using a free-form surface, a desired needle-like body can be suitably designed using a known three-dimensional CAD drawing apparatus prior to manufacturing. At this time, a physical model of the needle-shaped body is formed from the shape of the designed needle-shaped body and the characteristics of the needle-shaped body material, and a physical calculation is performed using a computer with the physical model considering the skin of the living body. By performing the simulation, it is possible to evaluate the shape of the needle-like body suitable for skin puncture before manufacturing the needle-like body.

  In addition, the shape of the side surfaces of the needle-like body and the arrangement of the needle-like bodies may be appropriately designed according to the use, material, manufacturing method and the like of the needle-like body. For example, the needle-like body side surface portion may be a prism and the tip portion may be a curved needle-like body.

  The needle-shaped material is not particularly limited, but a needle-shaped material applicable to a living body can be formed by using a medical silicone resin which is a biocompatible material, maltose, polylactic acid, dextran, carbohydrate, or the like. If a biocompatible material is used, even if a fine needle is broken and left in the body, there is an effect that it is harmless.

  The method for manufacturing the needle-shaped body may be any manufacturing method that can form the shape of the tip portion that is a characteristic configuration of the present invention. For example, a resist is applied to a substrate, the resist is patterned, and the patterning is performed. A manufacturing method in which the shape of the resist subjected to the above process is deformed and etching is performed from the direction in which the resist is applied to the substrate may be used, or a manufacturing method in which direct shaping is performed using laser light or the like from three-dimensional CAD data.

  When manufacturing an acicular body using etching, the shape of the tip can be controlled by adjusting the shape of a resist pattern used as an etching mask and the etching conditions of the substrate.

  In addition, by controlling the resist film thickness in the resist pattern shape, the radius of curvature of the needle-like tip after etching can be controlled. At this time, the larger the resist film thickness, the larger the radius of curvature of the needle-like body tip portion, and the smaller the resist film thickness, the smaller the radius of curvature of the needle-like body tip portion.

  In addition, as a method of deforming the resist shape, the resist is exposed and developed using a so-called gray mask using a mesh pattern that is below the resolution limit of the resist for a photomask used for resist photolithography, and the resist pattern is developed. A forming method may be used. By using the gray mask, the exposure intensity of the resist can be controlled, and the resist can be shaped according to the gray mask.

  The etching conditions can be adjusted by adjusting the etching parameters such as the type of etching gas, the output of the etching apparatus, the pressure in the chamber and the substrate cooling temperature, and other etching parameters. .

  As a method for producing the needle-shaped body, it is preferable that the needle-shaped body having the shape of the tip portion, which is a characteristic configuration of the present invention, is used as a mother mold, a replica plate is formed, and transfer processing molding is performed. By performing transfer processing molding, it is possible to select a material and manufacture a needle-like body without being stuck to the processing characteristics for molding the mother die. Therefore, for example, by using a medical silicone resin that is a biocompatible material, maltose, polylactic acid, dextran, carbohydrate, or the like, a needle-like body applicable to a living body can be formed. If a biocompatible material is used, even if a fine needle is broken and left in the body, there is an effect that it is harmless.

As transfer processing molding, a known transfer processing molding method may be appropriately selected and used. For example, a duplicate plate may be made by Ni electroforming or the like, and an imprint method using the duplicate plate, a hot embossing method, an injection molding method, an extrusion molding method, or a casting method may be performed.
By making a duplicated plate with high mechanical strength and multiple impositions, needles can be produced in large quantities and on a large screen with the same duplicated plate, thus reducing production costs and increasing productivity. Is possible.

Hereinafter, the method for producing the needle-shaped body of the present invention will be described with specific examples. Naturally, the manufacturing method of the acicular body of the present invention is not limited to the following examples, and includes other manufacturing methods that can be inferred from known materials in each step.
Further, the needle-like body of the present invention is not limited to the needle-like body created in the following embodiment, and may be manufactured by other methods capable of forming the shape of the tip portion which is a characteristic configuration. (For example, a manufacturing method in which a mother die is directly formed from three-dimensional CAD data using a laser beam or the like, and transfer processing is formed using the mother die) may be used.

<Example 1>
First, the shape of the needle-like body was designed.
As the shape of the needle-like body of the present embodiment,
With the base of the needle-shaped body as the origin,
The axial direction from the base to the tip of the needle is the Z axis,
An arbitrary axial direction perpendicular to the Z axis is defined as an X axis,
In a three-dimensional orthogonal coordinate system in which the axial direction perpendicular to both the Z axis and the X axis is the Y axis,
The side surface of the needle-like body is tapered,
For the region where the taper angle of the side surface of the needle-like body is 30 ° or less,
The coordinates on the curved surface of the tip of the needle-like body are assumed to have a shape that satisfies the following mathematical formula (FIG. 1).

  Hereinafter, an example of the method for producing a needle-shaped body of the present invention will be described with reference to FIG.

  First, a silicon wafer having a diameter of 4 inches and a thickness of 525 μm was prepared, and a positive photoresist (trade name: LA-900) was coated on the silicon wafer to a thickness of 20 μm (FIG. 2A).

  Next, a cylindrical resist pattern having a diameter of 5 μm and a height of 20 μm was formed by photolithography (FIG. 2B).

  Next, the resist pattern was hard baked in an oven at 180 ° C. for 1 hour. The resist pattern was thermally deformed by the hard baking process. When a cross section of the resist pattern was observed with a scanning electron microscope (hereinafter referred to as SEM), the cross-sectional projection image from the side of the resist shape after thermal deformation became a semicircular shape (FIG. 2 ( c)).

Next, using the resist pattern after thermal deformation as an etching mask, using a fluorocarbon-based gas as an etching gas, and using an inductively coupled plasma (hereinafter referred to as ICP), the shape of the resist pattern is the number Etching was performed to the extent that the design shape using “1” was satisfied (FIG. 2D).
At this time, the resist pattern used as an etching mask was reduced by silicon processing, and the diameter of the resist pattern became 15 μm. Further, as the resist pattern is reduced, the exposed silicon is also sequentially etched, and finally formed silicon has a conical shape having a tapered shape. In addition, the silicon wafer was etched up to 250 μm.

  From the above, the needle-shaped body of the present invention could be manufactured.

<Example 2>
The needle-shaped body manufactured in Example 1 was used as a mother mold, and transfer processing molding was performed.
First, the acicular body manufactured in Example 1 was used as a mother mold, and a nickel replica was produced by electrolytic plating. At this time, a nickel layer 30 nm formed by vapor deposition was used as a seed layer, and a nickel sulfamate solution was used as a plating solution at the time of electrolytic plating. Further, the pH of the plating bath was 4.7, the plating bath temperature was 50 ° C., and nickel was formed to a thickness of 400 μm (FIG. 3E).

  Next, after the nickel film was formed, the silicon and resist used as the mother mold were dissolved and removed with a potassium hydroxide aqueous solution at 90 ° C. and a 25 wt% concentration to complete a nickel replica having a concave / convex pattern of the silicon original plate ( FIG. 3 (f)).

  Next, hot press molding was performed on the PLA softened by heating at 170 ° C. using the above nickel replica. At this time, the indentation pressure of the nickel replica plate to PLA was 15 MPa, the holding time was 1 minute, and after the holding time had elapsed, the PLA and nickel replica plate were cooled to room temperature, and then the nickel replica plate was peeled off (FIG. 3 (g )).

  From the above, the needle-like body of the present invention composed of a biocompatible resin could be manufactured.

  The needle-shaped body of the present invention can be expected to be used as a fine needle used in a device for transporting drugs such as medicines, drug discovery, and cosmetics.

It is the schematic which shows an example of the acicular body of this invention. It is process drawing which shows an example of the method of manufacturing the acicular body of this invention. It is process drawing which shows an example of the method of manufacturing the acicular body of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Resist 2 ... Board | substrate 3 ... Resist pattern 4 ... Deformed resist pattern 5 ... Needle-like body 6 ... Duplicated plate 7 ... Needle-like body

Claims (6)

In the method for producing fine needles,
Applying a resist to the substrate;
Patterning the resist and forming a resist pattern;
Etching from the direction in which a resist is applied to the substrate, and a step of forming a needle-like body having an etched substrate and a tip formed of a curved surface and resist on the etched substrate.
A method for producing a needle-like body comprising: The curved surface of the front Kiharijotai tip bicubic curved, Coons curved surface, Bezier surface, B- spline surface, claims, characterized in that NURBS curved surface, a free curved surface selected from the group consisting of Gregory curved surfaces A method for producing the acicular body according to 1 . Etching from the direction in which a resist is applied to the substrate, and in the step of forming a needle-like body having a tip portion made of a resist and a curved shape on the etched substrate and the etched substrate,
With the base of the needle-shaped body as the origin,
The axial direction from the base to the tip of the needle is the Z axis,
An arbitrary axis direction orthogonal to the Z axis is defined as an X axis,
In a three-dimensional coordinate system in which the axis direction perpendicular to both the Z axis and the X axis is the Y axis,
The side surface of the needle-like body is tapered,
For the region where the taper angle of the side surface of the needle-like body is 30 ° or less,
In the range where the coordinates on the curved surface of the tip of the acicular body satisfy the following mathematical formula,
Etching is stopped. The method for manufacturing a needle-shaped body according to claim 1 or 2, wherein etching is stopped.
The resist pattern formed in the step of patterning the resist is a cylindrical resist pattern, and the cross-sectional projection image from the side surface of the cylindrical resist pattern is formed in a semicircular shape before the etching step. The method for producing a needlelike object according to any one of claims 1 to 3, further comprising a step of deforming. 5. The method of manufacturing a needle-shaped body according to claim 4, wherein the step of deforming the cylindrical resist pattern so that a cross-sectional projection image from the side surface has a semicircular shape is performed by heat. A needle-shaped body manufactured by the method for manufacturing a needle-shaped body according to any one of claims 1 to 5 is used as a matrix, a replica plate is formed, and transfer processing is performed. Method.