JP5173332B2 - Microneedle and microneedle manufacturing method - Google Patents

Description

  The present invention relates to a microneedle that is a fine structure.

  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 micron-order microneedles and administering the drug directly 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 micro-needles 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 part is several μm to several hundred μm, and the length of the protrusion is the length that penetrates the stratum corneum, which is the outermost layer of the skin, and does not reach the nerve layer, specifically about several tens μm to several hundred μm It is said that it is desirable.

  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 microneedle for the purpose of blood collection, a protrusion having a height of at least 350 μm is required due to the structure of the skin.

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

  In order to produce such a fine structure at a low cost and in large quantities, a transfer molding method represented by an injection molding method, an imprint method, a casting method, or the like is effective, but molding is performed in any method. In order to achieve this, it is necessary to have a prototype in which the desired shape is inverted, the aspect ratio (height or depth ratio to the width of the structure) is high like a microneedle, and the tip must be sharpened. In order to form a certain structure, the manufacturing process becomes very complicated.

  For example, as a method for producing a microneedle, a production method has been proposed in which a microneedle original plate is produced by X-ray lithography, a duplicate plate is produced from the original plate, and transfer molding is performed (see Patent Document 3).

In addition, a manufacturing method has been proposed in which a microneedle original plate is produced by machining, a duplicate plate is produced from the original plate, and transfer molding is performed (see Patent Document 4).
US Pat. No. 6,183,434 Japanese Patent Laid-Open No. 2005-21677 JP 2005-246595 A JP-T-2006-513811

When a minute structure such as a microneedle is manufactured / used, there is a problem that a place where stress is concentrated is damaged.
In particular, when puncturing an object having elasticity (for example, living skin), a tensile or compressive stress is greatly applied to the microneedle due to the elasticity of the target, and the vertical direction of the microneedle (from the base of the microneedle) Since a large stress is applied not only in the direction toward the tip) but also in the horizontal direction, the microneedles are easily damaged.

Further, if the needle diameter is simply increased in order to improve the strength, when used as a medical microneedle, the probability of stimulating a pain point during puncture increases.
If the needle diameter is increased, when a plurality of microneedles are arranged, the pitch between the microneedles cannot be reduced, and the number of microneedles per area cannot be increased.

  Therefore, the present invention has been made to solve the above-described problems, and an object thereof is to provide a microneedle capable of suppressing breakage due to stress from the horizontal direction.

According to the first aspect of the present invention, in the microneedle that is a fine structure, the base shape of the microneedle is an oval shape , and the major axis direction of the base shape of the microneedle is selected from any one point. A plurality of microneedles are arranged so that their radial directions are parallel to each other, and the arbitrary one point is located inside the outer circumference of the arrangement of the microneedles.
In this specification, “oval shape” means A) having at least one target axis, B) not intersecting, convex outward, closed and composed of a curved line on a plane. Defined as shapes that include not only elliptical shapes, egg shapes, oval shapes, but also part of the curve replaced with line segments (for example, rounded rectangular shapes), and teardrop-shaped shapes To do.

  The present invention described in claim 2 is the microneedle according to claim 1, which is made of a biocompatible material.

The present invention described in claim 3 is the microneedle according to claim 1 or 2 , wherein the longer the microneedle located on the outer peripheral side of the array, the larger the major axis in the base shape of the microneedle compared to the minor axis. It is the microneedle characterized by the above-mentioned.

The present invention is defined in claim 4, a micro Needle a microstructure, the base portion shape of the microneedles is oval shaped and the major axis direction of the base portion shape of the microneedles, optionally A method of manufacturing a microneedle in which a plurality of microneedles are arranged so that the radial direction from one point is parallel, and the arbitrary one point is located inside the outer periphery of the arrangement of the microneedles , A plurality of etching masks whose top projection is an oval shape and having a thickness distribution are arranged on the substrate so that the major axis direction in the oval shape of the etching mask is parallel to the radiation direction from any one point. and forming Te, the steps of said any point is located inside the outer periphery of the array of the microneedles, the etching mass And performing anisotropic etching on the substrate from the formed side to a method for producing a microneedle, characterized in that it comprises a.

The present invention described in claim 5 is the method of manufacturing the microneedle according to claim 4 , further comprising the step of making the manufactured microneedle as a mother mold and producing a replica from the mother mold, and the replica And a step of performing a transfer molding process using a plate.

The microneedle of the present invention is characterized in that the shape of the base of the microneedle is an oval shape.
According to the configuration of the present invention, since the base shape is an oval shape, the stress in the major axis direction of the oval shape can be relieved.
Therefore, by relaxing the stress from the horizontal direction, it is possible to suppress damage due to the stress from the horizontal direction.

Hereinafter, the microneedle of the present invention will be described.
The microneedle of the present invention is
The base shape of the microneedle is an oval shape.

By setting the base shape to an oval shape, it is possible to relieve the stress in the major axis direction of the oval shape out of the stress applied to the microneedles. Therefore, stress from the horizontal direction is relieved, and breakage due to stress from the horizontal direction can be suppressed.
For example, when the difference in strength due to the difference in the cross-sectional shape of the microneedle is compared, in the case of the same cross-sectional area, the elliptical shape with the major axis vs. minor axis of 6: 4 is longer The strength is 1.2 times or more the force acting in the direction.
In this specification, “oval shape” means A) having at least one target axis, B) not intersecting, convex outward, closed and composed of a curved line on a plane. Defined as shapes that include not only elliptical shapes, egg shapes, oval shapes, but also part of the curve replaced with line segments (for example, rounded rectangular shapes), and teardrop-shaped shapes To do.

  The microneedle of the present invention is preferably made of a biocompatible material. By using a material having biocompatibility, even if the needle-like body is damaged when applied to living body skin and a part of the needle-like body is left in the living body, the influence on the living body can be reduced. Examples of materials having biocompatibility include inorganic compounds such as Mg-based compounds and Ti-based compounds, polylactic acid, polyglycolic acid, polylactic acid glycolic acid copolymer, polycitric acid, polymalic acid, polyamino acid, maltose, Examples thereof include organic polymers having biocompatibility and biodegradability, such as dextran.

  In the microneedle of the present invention, a through hole may be formed in the microneedle or in the vicinity of the microneedle. By providing the through hole, it can be suitably used for a device configured to collect / supply body fluid / chemical solution through the through hole.

  In addition, the microneedle of the present invention is not particularly limited in shape, size, constituent material, and the like, and may be appropriately designed according to the application / specification. For example, when a microneedle is used for the purpose of transdermal administration, it is desirable that the diameter is several μm to several hundred μm and the length is about several tens μm to several hundred μm.

  The microneedle of the present invention may have a plurality of microneedles. At this time, the arrangement may be appropriately designed according to the specifications. For example, the microneedles may be arranged in a rectangular shape (FIG. 2A) or in a circular shape (FIG. 2B).

  In the microneedle of the present invention, it is preferable to arrange a plurality of microneedles so that the long axis direction in the shape of the base portion of the microneedle is parallel to the radial direction from any one point. When a plurality of lines are arranged, the stress due to the elasticity of the target is applied in the direction from the outer periphery to the inside of the array. Therefore, by arranging as described above, the major axis direction of the oval shape is arranged along the direction in which the stress due to the stretchability of the target is applied. Therefore, the microneedle is damaged by the stress due to the stretchability of the target. Can be suppressed. (Fig. 3, Fig. 4)

  When a plurality of microneedles are arranged, it is preferable that the major axis in the base shape of the microneedles is larger than the minor axis in the microneedles located on the outer peripheral side of the arrangement. In general, the larger the major axis is, the greater the mechanical strength in the major axis direction. Since the stress due to the stretchability of the target is more heavily applied to the microneedles located on the outer peripheral side of the array, the major axis in the base shape of the microneedle is larger than the minor axis for the microneedles located on the outer peripheral side of the array. In particular, damage at the outer periphery of the array can be suppressed. (Fig. 3, Fig. 4)

Hereinafter, a microneedle manufacturing method suitable for manufacturing the microneedle of the present invention will be described with reference to FIG.
The microneedle production method of the present invention comprises:
A step of forming an etching mask having a thickness distribution and a top projection on the substrate having an oval shape;
Performing anisotropic etching on the substrate from the side on which the etching mask is formed;
Is provided.

<Process for forming an etching mask having a thickness distribution and an oval projection on the substrate>
First, an etching mask having a top projection of an oval shape and a thickness distribution is formed.

  Etching to be described later by changing the etching mask in the thickness direction, making the thickness of the outer edge of the etching mask thinner than the thickness inside the etching mask, and continuously changing the thickness of the etching mask from the outer edge to the inside As the etching progresses, the mask is gradually removed from the outer edge of the etching mask, and a microscopic angle with a taper angle corresponding to the etching selectivity between the substrate and the etching mask (ratio of the etching rate of the substrate to the etching rate of the etching mask). A needle can be manufactured. (Fig. 1 (b))

  Moreover, the base part shape of the microneedle manufactured can be made into an oval shape by making the shape of an etching mask into an oval shape. (Fig. 1 (a), (a '))

A plurality of etching masks may be formed in an array. By forming a plurality of etching masks in an array, it is possible to manufacture a microneedle having a plurality of microneedles arranged in an array. At this time, the interval and the number of microneedles can be controlled by changing the pattern layout of the etching mask.
For example, a plurality of etching masks may be arranged so that the major axis direction in the oval shape of the etching mask is parallel to the radial direction from any one point.

  Moreover, the diameter of the microneedle to be manufactured can be controlled by changing the pattern diameter of the etching mask to be formed.

  The substrate is preferably made of a material having suitable processing characteristics in an etching process described later. For example, a silicon substrate may be used.

  As a mask material for the etching mask, it is sufficient that the etching rate of the etching mask is smaller than the etching rate of the substrate in the step of performing the etching described later, which is in close contact with the substrate.

  As a method for forming an etching mask on the substrate, a known patterning method may be used as appropriate. For example, as a patterning method, a method such as a method by exposure and development (the pattern portion can be controlled by a photomask to be used), a droplet discharge method (droplet discharge only to the pattern portion), or the like may be used.

  As a method of giving a thickness distribution to the etching mask, for example, reflowing the mask material, controlling the exposure amount of the mask material using a gray scale mask, and adjusting the drop amount of the mask material using an inkjet device , Etc. may be used.

<Step of performing anisotropic etching on the substrate from the side on which the etching mask is formed>
Next, etching is performed on the entire substrate from the side on which the etching mask is formed (FIG. 1C), and microneedles are manufactured (FIG. 1D).

  The etching method may be an anisotropic etching method in which the etching rate of the substrate and the etching rate of the etching mask are different, and a known method can be appropriately used. For example, you may perform dry etching using the dry etching apparatus using discharge methods, such as RIE, magnetron RIE, ECR, ICP, NLD, a microwave, and a helicon wave.

  At this time, the tip angle of the microneedle can be controlled by the etching selectivity of the substrate with respect to the etching mask. When the etching selectivity is high, the tip angle of the microneedle tends to be sharp and the height tends to be high. When the etching selectivity is low, the tip angle tends to be wide and the height tends to be low. The etching selectivity can be controlled by various conditions during etching (for example, pressure, process gas flow rate, process gas flow rate ratio, etc.) in addition to the selection of the material of the substrate and the etching mask.

  In addition, the mask is gradually removed, and finally the mask is converged to a small range and then completely removed to form microneedles, so that contamination due to etching mask dropping does not occur, In addition, a microneedle having a sharp tip shape can be manufactured.

  Further, the etching may be stopped after the etching mask remains (FIG. 1C) and the etching mask is peeled off. At this time, it becomes possible to manufacture a microneedle having an effect of reducing the chipping of the tip portion at the time of piercing, in which only the tip portion remains flat.

  From the above, the microneedle of the present invention can be manufactured. Although the method using an etching mask is shown here, the manufacture of the microneedle of the present invention is not limited to this, and the microneedle may be manufactured using other fine processing techniques. Here, examples of the fine processing technique include a fine cutting technique using an end mill and a processing technique using a laser beam.

  The microneedle manufacturing method of the present invention further includes a step of using the manufactured microneedle as a mother die, producing a duplicate plate from the mother die, and performing a transfer molding process using the duplicate plate. It is preferable. 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.

  Hereinafter, as an example, using FIG. 5 as a specific example, the microneedle 501 manufactured by the above-described manufacturing method is used as a mother mold, the mold layer 502 is formed, and the replica plate 503 is formed. Will be described.

<Microneedle transfer molding>
First, a template layer 502 for forming the duplicate plate 503 is formed on the surface on which the microneedles 501 are formed (FIG. 5A).

  Next, the microneedle 501 and the template layer 502 are separated to obtain a duplicate plate 503 (FIG. 5B).

  As a method of separating the microneedle 501 and the mold layer 502, separation by a physical peeling force or selective etching is used.

Next, the replica plate 503 is filled with a microneedle material (FIG. 5C).
The microneedle material is not particularly limited, but is preferably a material that is less irritating to the living body. Moreover, it is preferable to have flexibility so that the surface can be uniformly pressed against the curved surface. For example, a medical silicone resin, maltose, polylactic acid, dextran, or the like may be used as the microneedle material.

  Next, the microneedle material is released from the replica plate 503 to obtain a transfer-molded microneedle 504 (FIG. 5D).

<Example 1>
The microneedle manufacturing method of the present invention will be described with specific examples of the case where the shape of the etching mask is an elliptical dot pattern.

  First, a silicon wafer (thickness: 525 μm) was prepared as a substrate.

  Next, a general-purpose thick film photoresist (manufactured by Clariant, trade name: AZ PLP) as an etching mask is coated on the silicon wafer to a film thickness of 13 μm using a spray coating method, and a long axis of 120 μm is formed using a photolithography method. An elliptical dot pattern having a minor axis of 80 μm was formed.

  Next, the etching mask was heated in a clean oven at 150 ° C. for 30 minutes to perform reflow. The resist shape after reflow had a thickness distribution, and the thickest part of the resist at the center was 21.5 μm.

Next, the front surface of the substrate was etched until the etching mask on the substrate was completely removed by ICP (Inductively Coupled Plasma) etching using a fluorine-based gas.
At this time, as a result of measuring the etching rate of the etching mask and the silicon substrate, the etching selectivity between silicon and the etching mask was about 11.

  Next, the substrate after the entire surface etching was observed with a scanning electron microscope. It was confirmed that a cone-shaped microneedle having an elliptical bottom surface with a base axis having a major axis diameter of about 120 μm, a height of about 235 μm, and a tip angle of about 28 ° as viewed on the major axis side was formed.

<Example 2>
Microneedles were formed in the same manner as in Example 1. However, the etching masks were arranged in an array.

  The board | substrate which finished the whole surface etching was observed with the scanning electron microscope. The diameter of the major axis of the base is about 120 μm, the height is about 235 μm, and the tip angle seen on the major axis side is about 28 °. confirmed.

<Example 3>
Hereinafter, a method for producing microneedles by transfer molding will be described.

A nickel layer having a thickness of 300 nm was formed on the microneedle manufactured in Example 2 by vapor deposition, and 1 mm of nickel was formed by plating using this nickel layer as a seed layer.
Next, a silicon substrate was dissolved using a potassium hydroxide aqueous solution having a concentration of 25 wt% and a liquid temperature of 90 ° C. to produce a replica plate made of nickel.

  When this duplicate plate was used for transfer molding by the imprint method using maltose, dextran, and polylactic acid as materials, it was confirmed that microneedles having the same shape as the original plate were formed.

  The microneedle of the present invention can be applied not only to medical treatment but also to various fields that require fine needle-like structures, and is also useful as a microneedle for use in, for example, MEMS devices, drug discovery, cosmetics, and the like.

It is sectional drawing which shows the microneedle manufacturing method of this invention. It is a figure which shows an example of the microneedle of this invention. It is a figure which shows an example of the microneedle of this invention. It is a perspective view which shows an example of the microneedle of this invention. It is sectional drawing which shows the transfer molding process process in the microneedle manufacturing method of this invention.

Explanation of symbols

101, 201, 301, 401 ... Substrate 102, 202, 302 ... Etching mask 103 ... Etching mask (after deformation)
104, 402, 501, 504... Microneedle 502... Mold layer 503.

Claims (5)

In microneedles that are fine structures,
The base shape of the microneedle is an oval shape, and
Arranging a plurality of microneedles such that the long axis direction in the base shape of the microneedles is parallel to the radial direction from any one point; and
The microneedle characterized in that the one arbitrary point is located inside the outer periphery of the microneedle array. The microneedle according to claim 1,
A microneedle comprising a biocompatible material. The microneedle according to claim 1 or 2,
A microneedle characterized in that a long axis in a base shape of a microneedle is larger than a short axis in a microneedle located on the outer peripheral side of the array. A micro Needle a microstructure, the base portion shape of the microneedles is oval shaped and the major axis direction of the base portion shape of the microneedles, and parallel with the radial direction from an arbitrary point A method of manufacturing a microneedle in which a plurality of microneedles are arranged so that the arbitrary one point is located inside an outer periphery of the arrangement of the microneedles ,
A plurality of etching masks whose top projection is an oval shape and having a thickness distribution are arranged on the substrate so that the major axis direction in the oval shape of the etching mask is parallel to the radiation direction from any one point. A step in which the arbitrary one point is located inside the outer periphery of the array of the microneedles, and
Performing anisotropic etching on the substrate from the side on which the etching mask is formed;
Method for producing a microneedle, characterized in that it comprises a. It is a manufacturing method of the microneedle of Claim 4, Comprising:
Furthermore,
Using the manufactured microneedle as a master, producing a replica from the master, and performing a transfer molding process using the replica,
A method for producing a microneedle, comprising: