JP4978245B2 - Needle-shaped body, needle-shaped body manufacturing method, and drug transport device - Google Patents

Description

  The present invention relates to an acicular body, a method for producing the acicular body, and a drug transport device using the acicular 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 of efficiently absorbing these drugs into the body, there is a method of perforating the skin using a fine needle-like body (hereinafter simply referred to as a needle-like body) on the order of μm and directly administering the drug into the skin. Attention has been paid.

  The acicular body forms a perforation in the epidermis having a barrier function (more specifically, the stratum corneum formed in the outermost layer of the epidermis), and normal percutaneous absorption from the perforation is inhibited by the barrier function of the epidermis. Drugs that cannot be administered can be absorbed into the body. 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 here is sufficiently thin to perforate the skin, and the tip angle, the length that penetrates the stratum corneum that is the outermost layer of the skin and does not reach the nerve layer, Specifically, the diameter of the needle-shaped body is about several μm to 100 μm, the tip angle of the needle-shaped body is 30 ° or less, and the length of the needle-shaped body is several tens μm to several hundred μm. It is considered desirable to be a degree.

  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).

Further, as a method for producing a needle-like body, a method utilizing a photolithography method is known (see Patent Document 3).
US Pat. No. 6,183,434 Japanese Patent Laid-Open No. 2005-21677 JP 2002-239014 A

  However, when puncturing the skin, the needle-shaped body may be damaged or deformed. The breakage / deformation of the needle-shaped body occurs due to a decrease in the mechanical strength of the needle-shaped body, and causes a decrease in drug dosage.

  In particular, in order to penetrate the stratum corneum, when the needle-shaped body has a high aspect ratio (the ratio of the height to the width of the needle) and the tip angle is sharpened, the problem of the decrease in the mechanical strength of the needle-shaped body is Become prominent.

  In particular, when a biocompatible resin is used for the needle-like body in order to reduce the influence on the human body, there are limitations on the materials that can be selected, and it is difficult to suppress breakage / deformation only by the strength of the material. .

  In particular, when the needle-like body is formed into a plurality of regularly arranged shapes (for example, the needles are arranged in an array) in order to enhance the drug administration effect, the load when pushing is different for each needle. Since the bias cannot be corrected, a part or the whole of the needle-like body is damaged, and the puncture state of the skin varies, and as a result, it is difficult to obtain a stable drug administration or pharmacological effect. Therefore, there arises a problem that it is difficult to improve the drug administration effect and reproducibility.

  In particular, when the needle-like body is pushed into the skin without using a dedicated device or instrument, there are many variations in the skin puncture situation. When the needle-like body is pushed into the skin by hand, the load applied to the needle-like body is biased, and the load is concentrated on some needle-like bodies. For this reason, the needle-like body at the place where the load is concentrated is broken or deformed, resulting in a decrease in drug dosage. In addition, the load bias varies greatly depending on the location and state of the skin to be pushed in, and the degree of force applied, so the degree of breakage and deformation of the needles changes each time it is pushed in, resulting in the reproducibility of the drug administration effect. Leading to a decline.

  Therefore, the present invention has been made to solve the above-described problem, and it is possible to correct a load imbalance on the needle-like body that occurs during puncturing, thereby suppressing breakage and deformation of the needle-like body. An object of the present invention is to provide a needle-like body that can provide a stable drug administration effect.

The present invention according to claim 1 is a fine needle-like body, comprising a substrate, a fine needle that punctures the skin, and an auxiliary pattern in the vicinity of the fine needle, on the same surface of the substrate. The fine needle and the auxiliary pattern are formed, and the height of the auxiliary pattern is higher than the height of the needle.

  The present invention described in claim 2 is the needle-shaped body according to claim 1, wherein the auxiliary pattern is an auxiliary pattern surrounding the periphery of the needle.

  The present invention according to claim 3 is the needle-like body according to claim 1 or 2, wherein a plurality of fine needles are regularly arranged. It is.

  A fourth aspect of the present invention is a drug delivery device using the needle-shaped member according to any one of the first to third aspects.

According to a fifth aspect of the present invention, in the method for manufacturing a fine needle-shaped body, a step of applying a resist to a substrate, a step of patterning the resist together with a needle and an auxiliary pattern, and a direction of applying the resist And etching the substrate, the fine needle and the auxiliary pattern are formed on the same surface of the substrate, and the height of the auxiliary pattern is higher than the height of the needle. It is a needle- shaped object manufacturing method characterized by manufacturing the needle-shaped object which has .

  The present invention described in claim 6 is a method for manufacturing a needle-like body, wherein the needle-like body produced by the method for manufacturing a needle-like body according to claim 5 is used as a prototype, and transfer processing is performed.

  The acicular body of the present invention includes an auxiliary pattern, and the height of the auxiliary pattern is higher than the height of the needle. According to the configuration of the present invention, when the skin is punctured, the auxiliary pattern comes into contact with the skin prior to the needle. Therefore, the direction in which the needle enters the skin can be corrected by the auxiliary pattern. Therefore, when the skin is punctured, the load applied to the needle can be prevented from being biased, and the needle-like body can be prevented from being damaged or deformed, and a stable drug administration effect can be obtained.

Hereinafter, the acicular body of the present invention will be described.
The needle-shaped body of the present invention is
A fine needle that punctures the skin,
An auxiliary pattern in the vicinity of the fine needle,
The height of the auxiliary pattern is higher than the height of the needle.

  The needle-shaped body of the present invention forms an auxiliary pattern (FIGS. 1 and 102) around the needle for drug administration (FIGS. 1 and 101) to prevent the load applied to the needle-shaped body during pressing. As a result, it is possible to uniformly disperse the load applied to the needle-like body during pushing. As a result, it is possible to correct a load bias applied during puncturing, suppress damage to the needle-like body, and obtain a stable drug administration effect.

  At this time, since the shape of the auxiliary pattern needs to prevent a load from being applied to the needle-like body when it is pushed into the skin, the shape of the needle-like body against the skin before the needle-like body contacts the skin. It is necessary to correct the approach direction, and specifically, it is necessary to have a height higher than the needle-like body.

  The auxiliary pattern is preferably an auxiliary pattern surrounding the needle. At this time, the auxiliary pattern acts as an enclosure for stopping the chemical solution, and can prevent the applied chemical solution from flowing out of the needle-like body. For this reason, an auxiliary pattern can be utilized as a container for medicine quantification.

Further, the auxiliary pattern may be arranged such that a part of the peripheral part around the pattern part of the needle-like body or the shape of the needle-like body at the outermost peripheral part has a higher strength.
For example, a columnar structure (FIGS. 2 and 104) (FIGS. 2 and 105) or a spherical structure (FIGS. 2 and 106) may be used. In this case, it is possible to reduce the area of the auxiliary pattern that contacts the skin at the time of puncturing, as compared to the case surrounding the needle, to reduce the dispersion of the pushing pressure, and to reduce the puncturing ability of the needle-shaped body Therefore, it becomes possible to correct the bias of the pushing pressure.

  The material constituting the needle-like body is not particularly limited, but a needle-like body applicable to the living body is formed by using biocompatible material such as medical silicone resin, maltose, polylactic acid, dextran, carbohydrates, etc. I can do it. 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 constituent material of the auxiliary pattern is not limited to the material like the needle-like body, and a material different from the needle-like body can be used depending on the manufacturing method.

As a method for manufacturing the needle-shaped body, any method may be used as long as it can form a needle-shaped body for drug administration and an auxiliary pattern for load equalization.
For example, after forming a processing hole for forming a needle-shaped body pattern and an auxiliary pattern on a substrate using a laser, a method of collectively molding the needle-shaped body pattern and the auxiliary pattern that are reversed by transfer molding,
Using a photomask (for example, a gray mask) that controls the exposure by applying a resist on a silicon wafer and adjusting the pattern density below the resist resolution limit, the resist pattern and auxiliary pattern for forming needle-like bodies Examples include a method of forming a resist pattern for formation and processing the silicon wafer by dry etching based on the resist pattern.

  In particular, a manufacturing method in which a resist pattern is formed and etched is preferable as the method for manufacturing the needle-shaped body of the present invention. In the step of forming the resist pattern, the arrangement of the needle and the auxiliary pattern can be determined at a time, so that the needle and the auxiliary pattern can be arranged with high accuracy to manufacture the needle-like body.

  Further, the produced needle-like body may be used as a prototype, and transfer processing molding may be performed.

  At this time, as transfer processing molding, a known transfer processing molding method may be appropriately selected and used. For example, by using a Ni electroforming method, a method using a molding resin, etc., a duplicate plate is produced, and an imprint method using the duplicate plate, a hot embossing method, an injection molding method, an extrusion molding method, a casting method, etc. are performed. Also good.

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. I can do it.
In addition, since the shape can be transferred regardless of the processing characteristics of the material, a needle-like body made of a general resin can be manufactured. In particular, a needle-like body made of a biocompatible resin can be formed. As the biocompatible resin, for example, medical silicone resin, maltose, polylactic acid, dextran, or the like may be used.

  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 needle-shaped 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.

<Example 1>
First, a silicon wafer (FIG. 3.201) was prepared. At this time, the silicon wafer has a thickness of 525 μm and a diameter of 4 inches, and is generally used in a semiconductor manufacturing process.

  Next, a positive photoresist (trade name: LA-900) was applied on the silicon wafer. (FIG. 3 202) At this time, the film thickness of the resist was measured and found to be 20 μm.

Next, a resist pattern for forming a needle-like body and a protective pattern was formed from this resist by a photolithography method.
At this time, the photomask used is a pattern smaller than the resolution limit of LA-900, specifically, a photomask mask (gray mask) in which squares having a diameter of 0.5 μm are arranged at an arbitrary density, and the exposure amount. Was adjusted.

  In addition, the shape of the resist pattern for needle-like body formation at this time was a hemispherical shape having a diameter of 100 μm and a height of 20 μm (FIG. 3, 203). The resist patterns for forming the needle-like bodies were arranged with a pitch (distance between the centers of adjacent resists) of 200 μm and five in each of the vertical and horizontal directions.

  Further, the shape of the protective pattern forming resist pattern at this time is a quadrangular prism shape (FIGS. 3 and 204) having a side length of 150 μm and a height of 20 μm, and four locations on the diagonal line of the resist pattern area for forming a needle-like body Arranged. The auxiliary pattern was arranged so that the center of the auxiliary pattern was located at a distance of 300 μm from the center of the needle-like body forming pattern.

  Next, the silicon wafer was processed by plasma etching using inductively coupled plasma (hereinafter referred to as ICP) using the protective pattern forming resist pattern and the needle-shaped body forming resist pattern as an etching mask. As the etching gas, a mixed gas of fluorocarbon gas and oxygen gas was used.

  At this time, the diameter of the hemispherical resist pattern for forming the needle-like body pattern is reduced by etching as the etching progresses (FIG. 3, 205), and disappears completely when the silicon wafer is processed to 250 μm. . As a result, a needle-like body (FIG. 3, 207) having a root width of 100 μm and a height of 250 μm was formed. On the other hand, the resist pattern for forming the auxiliary pattern was also reduced by ICP etching (FIGS. 3 and 206), and the resist pattern disappeared completely when the silicon processing was completed, but the resist shape is a square pillar, The shape of the auxiliary pattern formed by ICP etching was also a quadrangular column (FIG. 3, 208) having a side of 150 μm and a height of 250 μm.

  The acicular body according to the present invention was completed through the above production steps.

  As an advantage of this embodiment, by changing the ICP etching conditions of silicon, such as the mixture ratio of fluorocarbon gas and oxygen gas, ICP output, etching bias, substrate cooling temperature, etc. The side wall angle of the shaped body can be adjusted, and the needle-like body and the auxiliary pattern can be formed in a lump.

<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. Moreover, the pH of the plating bath was 4.7, the temperature of the plating bath was 50 ° C., and nickel was deposited to a film thickness of 400 μm.

  Next, after the nickel film is formed, the silicon and resist used as the mother mold are dissolved and removed with a potassium hydroxide aqueous solution at 90 ° C. and a concentration of 25 wt%, and a nickel replica plate having a concave / convex pattern of the silicon original plate (FIGS. 3 and 209). ) Was completed.

  Next, hot press molding was performed on the polylactic acid softened by heating at 170 ° C., using the above nickel replica. At this time, the indentation pressure of the nickel replication plate into the polylactic acid is 15 MPa, the holding time is 1 minute, and after the holding time has elapsed, after the polylactic acid and the nickel replication plate are cooled to room temperature, the nickel replication plate is peeled off and biocompatible. The acicular body of the present invention (FIGS. 3 and 210) composed of polylactic acid, which is an adhesive resin, could be produced.

  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 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.

Explanation of symbols

DESCRIPTION OF SYMBOLS 101 ... Acicular body 102 ... Auxiliary pattern 103 concerning this invention ... Substrate 104, 105, 106 ... Example of auxiliary pattern shape and arrangement concerning this invention 201 ... Silicon wafer 202 ... Resist layer 203 ... Needle-form forming resist pattern 204... Auxiliary pattern-forming resist pattern 205... Needle-form forming resist pattern 206 reduced by etching... …… Auxiliary pattern 209 …… Ni replica plate 210 made from silicon original plate …… Acicular body according to the present invention formed in a batch based on the Ni replica plate

Claims (6)

In fine needles,
A substrate,
A fine needle that punctures the skin,
An auxiliary pattern in the vicinity of the fine needle,
The fine needle and the auxiliary pattern are formed on the same surface of the substrate,
The needle-like body, wherein the auxiliary pattern has a height equal to or higher than a needle height. The acicular body according to claim 1,
The auxiliary pattern is an auxiliary pattern surrounding the needle. The needle-shaped body according to claim 1 or 2,
A needle-like body in which a plurality of fine needles are regularly arranged.   A drug transport device using the needle-shaped body according to any one of claims 1 to 3. In the method for producing fine needles,
Applying a resist to the substrate;
Patterning the resist together with a needle and an auxiliary pattern;
And a step of etching the substrate from the direction in which the resist is applied ,
The fine needle and the auxiliary pattern are formed on the same surface of the substrate, and a height of the auxiliary pattern is higher than the height of the needle to produce a needle-like body. A method for producing a needle-like body. A needle-shaped body manufacturing method, wherein the needle-shaped body manufactured by the needle-shaped body manufacturing method according to claim 5 is used as a prototype, and transfer processing molding is performed.