JP5412045B2 - Acicular body array and array manufacturing method thereof - Google Patents

Description

  The present invention relates to an acicular array having a plurality of acicular bodies as 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 easily administer the drug without causing pain to the human body. However, depending on the type of drug, there are drugs that are difficult to administer by the transdermal absorption method. As a method for efficiently absorbing these drugs into the body, attention has been focused on a method of perforating the skin using a needle-like array containing micron-order needles and directly administering the drug into the skin. According to this method, it is possible to simply administer a drug subcutaneously without using a special device for dosing (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 acicular body is several μm to several hundred μm, and the length of the acicular body is a length that penetrates the stratum corneum that is the outermost layer of the skin and does not reach the nerve layer, specifically several tens μm to several It is desirable that the thickness is about 100 μm.

  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 to infiltrate the chemical solution, a length of at least 20 μm or more is required. Further, when manufacturing an acicular array for the purpose of blood collection, a acicular 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 acicular array must be a material that does not adversely affect the human body even if the damaged acicular body remains in the body. Biomedical resins such as medical silicone resins, maltose, polylactic acid, and dextran are considered promising (Patent Document 2).

  In order to manufacture such a needle array at a low cost and in large quantities, a transfer molding method typified by an injection molding method, an imprinting method, a casting method, etc. is effective. In order to do this, it is necessary to have a prototype in which the desired shape is inverted, and the aspect ratio (ie, the ratio of the height to the width of the structure or the depth) is high, and the tip is sharp. In order to form a structure that needs to be made, the manufacturing process becomes very complicated.

  For example, as a method for manufacturing an acicular array, a manufacturing method is proposed in which an original plate of an acicular array is produced by X-ray lithography, a duplicate plate is produced from the original plate, and transfer processing is performed (Patent Document 3). .

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

  An object of the present invention is to provide an acicular array that can be punctured efficiently and that can reduce needle breakage.

Means for solving the above problems are as follows:
(1) An acicular array comprising a substrate and a plurality of acicular bodies formed on the first surface of the substrate,
The plurality of needle-like bodies are integrally formed on the first surface of the base body,
The density of the needle-like body varies depending on the portion of the first surface,
The plurality of needles have the same height;
A needle array comprising the substrate and the plurality of needles is formed from a biocompatible biodegradable material selected from maltose, dextran and polylactic acid ; and
The density of the needle-like bodies at the end of the first surface is increased at any location across the outer periphery of the end relative to the density of the needle-like bodies at the center of the first surface. An acicular array characterized by:
(2) A method for producing a needle-shaped body array comprising a base and a plurality of needle-shaped bodies formed on the first surface of the base,
Forming an etching mask having a dense distribution on the first surface of the substrate;
Performing anisotropic etching on the first surface of the substrate to integrally form a plurality of needles having the same height and different densities on the first surface;
With
The density of the needle-like bodies at the end of the first surface is increased at any location across the outer periphery of the end relative to the density of the needle-like bodies at the center of the first surface. A method for producing an acicular array characterized by:
( 3 ) The method for producing the needle-shaped body array according to ( 2 ),
Furthermore, the manufactured needle-shaped body array is used as a mother mold, and a process for producing a duplicate plate in which the needle-shaped array is inverted from the mother mold to the mother mold;
Performing transfer processing molding using the duplicate plate;
A method for producing a needle-shaped body array comprising:
It is.

  The present invention provides a needle-like body array that can be punctured efficiently and that can reduce needle breakage.

1. Acicular body array The acicular body of the present invention will be described below.

  FIGS. 1A and 1B are diagrams schematically showing an acicular array according to the present invention. FIG. 1A is a plan view of an acicular array according to the present invention, and 1B is a cross-sectional view taken along line I-I in FIG. As shown in FIGS. 1 (a) and 1 (b), an acicular array 1 according to the present invention comprises a base 2 and a plurality of needles 3 formed on the first surface of the base 2. The density of the needle-like bodies 3 varies depending on the portion of the first surface. In particular, the needle-like body array 1 preferably has a higher density of the needle-like bodies 3 at the end of the first surface than the density of the needle-like bodies 3 at the center of the first surface. 1 (a) and 1 (b) is an example of a needle array having such a dense distribution.

  The present invention is provided by the inventors of the present invention assuming a cause of breakage of the needle-like body in the needle-like body array and devising means for solving the cause based on the cause. That is, when the needle-like bodies are arranged in an array on the base and the needle-like body is used as a needle portion to puncture the target, the first surface of the needle-like body array including the needle-like bodies It is conceivable that the puncture state is different between the central part and the end part. In particular, when puncturing a material having elasticity, for example, living skin, a tensile stress acts greatly in the surface direction at the end of the needle array due to the elasticity of the object, whereas Stress is hard to work at the part. In addition, when the needle-like bodies are arranged in an array at the same pitch, the number of adjacent needles is small at the end of the first surface, whereas the number of adjacent needles is large at the center portion. It may be difficult for the body to puncture the object.

  In order to make such a puncture state uniform over the first surface of the needle-like body array, it is also conceivable to change the height of the needle-like body depending on the part. However, in order to adjust the height, in many cases, it is necessary to change the production conditions of the needle-like body for each part. In addition, at the end of the first surface of the acicular array, the stress acting in parallel with the first surface is greater than that in the central portion, and the acicular body is considered to be easily damaged.

  Further, if the pitch between the needles is simply widened, the number of needle-like bodies per unit area is reduced and the total number of punctures is reduced. In addition, since the force applied to each piece increases, it becomes difficult to withstand, for example, a lateral force, and as a result, the needle-like body is broken or chipped, and is easily damaged. In addition, if the pitch between the needles is simply reduced, the number of needle-like bodies per unit area increases, which makes it difficult to puncture.

  The inventors adjust the stress applied to all the needle-shaped bodies included in the needle-shaped body array by changing the density of the needle-shaped bodies depending on the portion of the first surface of the needle-shaped body array. As a result, the present invention has been found. Thereby, it becomes possible to adjust the puncture state of each needle-like body in the needle-like body array. For example, by reducing the density of the needles at the center of the first surface and increasing the density of the ends, the puncture ability of the needles is not concentrated on the ends, and the needles array It is possible to efficiently use all the needle-like bodies over the entire first surface.

  In addition, by increasing the density of the end of the first surface where the stress is concentrated, the stress acting on each side is reduced, and the needle-like body at the end where a large force acts in the lateral direction is prevented from being damaged. It becomes possible.

  As used herein, “density” means the number of needles per region arbitrarily selected on the first surface of the needle array. As used herein, “the degree of density is different” and “having a distribution in the density” means that the number of needle-like bodies is different between at least two regions arbitrarily selected on the first surface.

  The material for the needle-like body array is not particularly limited as long as it has sufficient mechanical properties to hold the needle-like body. For example, metals such as stainless steel, silicon, Mg-based compounds and Ti-based compounds, for example, inorganic materials such as quartz and ceramics, biocompatible materials such as medical silicone resins, such as polylactic acid, polyglycolic acid, poly Biodegradable materials with biocompatibility such as lactic acid glycolic acid copolymer, polycitric acid, polymalic acid, polyamino acid, maltose, dextran, and other organic materials such as other biocompatible and biodegradable polymers And so on.

  When the needle-shaped body array is applied to living body skin, the material of the needle-shaped body array preferably has biocompatibility, and further has biocompatibility and biodegradability. More preferred. In addition, it is also preferable that at least the needle-like body is formed of a material having biodegradability. By using a material having biodegradability, the needle-like body is damaged when applied to living body skin. Even if the part is left in the living body, the influence on the living body can be reduced.

  The needle-like bodies included in the needle-like body array may be molded using the same type of material as the base, or may be molded using a different type of material from the base. When using different types of materials, the materials used for the substrate may be, for example, silicon, stainless steel and polycarbonate, and the materials used for the needles are, for example, polylactic acid, polyglycolic acid And maltose. For example, when silicon is used as a base and polylactic acid is used as a needle-like body, for example, only a polylactic acid needle-like body may be selectively hot-pressed on a silicon substrate.

  The shape of the needle-shaped body array may be freely designed depending on the application, and the needle-shaped body of the present invention is not particularly limited in shape, size, material constituting the material, and the use and / or specification. Depending on the design, it may be appropriately designed. For example, when it is used for the purpose of promoting percutaneous absorption of a physiologically active substance or for the purpose of taking a substance in a living body percutaneously out of the living body, it is provided in an acicular array from the viewpoint of skin puncture performance. The tip of the needle-like body has a sharp cone shape, the root width is several μm to several hundred μm, the length is about several tens μm to several hundred μm, and there is no constriction or step on the side wall of the needle-like body Is desirable.

  Moreover, the needle-shaped object array of the present invention may have a through hole in the needle-shaped object or in the vicinity of the needle-shaped object. By providing the through-hole, it can be suitably used as a device having a configuration in which body fluid and / or chemical liquid is collected and / or supplied through the through-hole.

  The needle-shaped array may be directly manufactured by a method known per se, for example, precision machining or the like, and is manufactured by transfer molding using a mold or a duplicate plate by a method known per se. Also good. Any such manufacturing method is within the scope of the present invention. Hereinafter, the manufacturing method of the said acicular body array is demonstrated.

2. Method for manufacturing needle array The needle array according to the present invention includes a step of forming an etching mask having a dense distribution on the first surface of the substrate, and anisotropic etching on the first surface of the substrate. What is necessary is just to manufacture by the process to perform.

  Hereinafter, an example of a needle-shaped object manufacturing method suitable for manufacturing the needle-shaped object array will be described with reference to FIG. 2 schematically showing a part of the substrate.

<Process for forming etching mask on substrate>
First, as shown in FIGS. 2A and 2A, an etching mask 102 is formed in an array on the first surface of the substrate 101 so as to correspond to the position of the needle-like body to be formed. 2A is a plan view from above the first surface of the substrate 101, and FIGS. 2A to 2D are cross-sectional views taken along line II-II in FIG. 2A. is there.

  The etching mask 102 may be arranged so as to have a different density depending on the portion of the first surface of the substrate 101. Preferably, it is formed so that the density of the needle-like bodies at the end of the first surface is greater than the density of the central portion of the first surface. That is, the etching mask 202 is not arranged at equal intervals on the first surface of the substrate 201 as shown in FIG. 3A, but the portion of the first surface of the substrate 201 as shown in FIG. It is preferable to arrange the etching mask 202 by changing the density by the above.

  Further, as shown in FIG. 2B, the thickness of the etching mask 103 is changed in the thickness direction so that the thickness around the edge of the etching mask 103 becomes thinner than the thickness of the center of the etching mask 103. It is also preferable to continuously change the thickness of the etching mask 103 from the edge toward the edge. Thus, as the etching process described later proceeds, the etching mask 103 is gradually removed from the outside, so that the etching selectivity between the substrate 101 and the etching mask 103 (the etching rate of the substrate 101 with respect to the etching rate of the etching mask 103). It is possible to manufacture a needle-like body array having a taper angle corresponding to the ratio.

  As described above, it is possible to control the density of the needle-shaped body to be manufactured by arranging the density of the etching mask 102 or 103 so as to vary depending on the portion of the first surface. In particular, when the density of the etching mask 102 or 103 is small at the center of the first surface and large at the end, it is possible to manufacture an acicular array having a pitch reflecting the mask pattern. Moreover, the diameter of the needle-shaped body manufactured can be controlled by changing the pattern diameter of the etching mask to be formed.

  The substrate 101 only needs to be a material having processing characteristics suitable for the etching process described later. For example, a silicon substrate, such as a single crystal silicon substrate, may be used.

  As a mask material for the etching masks 102 and 103, it is sufficient that the etching rate of the etching mask 102 or 103 is smaller than the etching rate of the substrate 101 in the step of performing the etching described later, which is in close contact with the substrate 101 described above.

  As a method for forming the etching mask 102 on the substrate 101, a known patterning method may be used as appropriate. For example, as a patterning method, a method by exposure and development (that is, a method that can control the pattern portion with a photomask to be used), a droplet discharge method (that is, a method that discharges droplets only to the pattern portion), or the like may be used. .

  Examples of a method for providing the etching mask 102 with a thickness distribution include a method of reflowing the mask material, a method of controlling the exposure amount of the mask material using a gray scale mask, and a droplet dropping amount of the mask material using an inkjet apparatus. You may use methods, such as the usage adjusted by.

<Step of performing anisotropic etching on the substrate from the side on which the etching mask is formed>
After the etching mask 102 or 103 is formed on the substrate 101, the process proceeds to the etching step. As shown in FIGS. 2C and 2D, in the etching process, the etching is performed over the entire first surface from the first surface side of the substrate 101 on which the etching mask 102 or 103 is formed. (FIG. 1C), the needle-like body 104 is manufactured (FIG. 1D).

  The etching method used in the present invention may be an anisotropic etching method in which the etching rate of the substrate 101 and the etching rate of the etching mask 102 or 103 are different, and a known method can be used as appropriate. Such a method includes, for example, dry etching using a dry etching apparatus using a discharge method such as RIE, magnetron RIE, ECR, ICP, NLD, microwave, and helicon wave.

  At this time, the tip angle of the needle-like body 104 can be controlled by the etching selectivity of the substrate 101 with respect to the etching mask 102 or 103. When the etching selection ratio is high, the tip angle of the needle-like body 104 is 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 and process gas flow rate, in addition to selection of materials for the substrate 101 and the etching mask 102 or 103.

  Further, the etching mask 102 or 103 is gradually removed, and finally the etching mask 102 or 103 is converged to a minute range and then completely removed. It is possible to manufacture the needle-like body 104 having a sharp tip shape without causing contamination due to the dropout of 102 or 103.

  Alternatively, the etching may be stopped while the etching mask 102 or 103 remains (FIG. 1C), and the etching mask 102 or 103 may be peeled off. Thereby, a needle-like body having a flat portion at the tip portion is formed. Such a needle-shaped body can reduce chipping at the tip during piercing.

  From the above, the acicular array according to the present invention can be manufactured. Although the method using the etching mask 102 or 103 is shown here, the manufacture of the needle-shaped array of the present invention is not limited to this, and may be manufactured using other fine processing techniques. Examples of the micromachining technique include a micromachining technique using an end mill and a machining technique using a laser beam.

  The method for manufacturing a needle-shaped body array according to the present invention further includes a step of using the manufactured needle-shaped body array as a mother die, producing a duplicate plate from the mother die, and performing transfer processing molding using the duplicate plate. It is preferable to provide a process. By producing a replica plate with high mechanical strength that is integrally molded, it is possible to manufacture a large number of needle-shaped object arrays with the same replica plate, which can reduce production costs and increase productivity. is there. In addition, since the transfer material can be selected without considering processing characteristics for microfabrication, in particular, a needle-like array formed of a biocompatible material can be preferably manufactured.

  Hereinafter, specifically as an example, using FIG. 4, the needle-shaped body array 401 manufactured by the above-described manufacturing method such as etching is used as a mother mold, a mold layer 402 is formed, and the obtained mold layer 402 is a duplicate plate. The transfer processing molding of the needle-shaped body array that is used as 403 will be described.

<Needle transfer processing molding>
First, the template layer 402 is formed on the first surface of the needle-like body array 401 on which the needle-like body 400 is formed (FIG. 4A).

  Next, the acicular array 401 and the template layer 402 are separated to obtain a duplicate plate 403 (FIG. 4B). As a method for separating the needle-like body 401 and the mold layer 402, separation by a physical peeling force or selective etching may be used.

  Next, the replica plate 403 is filled with the needle-shaped body array material (FIG. 4C). The needle array material is not particularly limited, and may be any material that can generally be transferred and molded. The needle-shaped materials listed in the section “1. Needle-shaped array” described above. It may be a body array material. In particular, when forming an acicular array for use with a living body, a material that is hypoallergenic to the living body is preferable. Moreover, it is also preferable that the finally obtained needle-like body array has flexibility so that the entire contact surface can be uniformly pressed against the curved surface.

  Next, the cured needle array material is released from the replica plate 403 to obtain a needle array 404 (FIG. 4D).

  The template layer material (i.e., the replica plate material) may be any material known per se suitable for obtaining the desired replica plate 403, for example, shape conformability capable of transferring the needle array 401. A material considering transferability, durability, and releasability in transfer processing molding may be selected. For example, a high molecular compound such as an elastomer such as a urethane resin or a silicone resin may be used. Further, for example, a metal material such as nickel, an aluminum alloy, a copper alloy, or an iron alloy may be used. Although not limited to this, for example, silicone resin is suitable as an inexpensive and low-risk material. Further, in order to remove impurities in the duplicate plate material, the duplicate plate material may be purified before being used in the transfer molding process.

  In addition, heating and / or cooling may be carried out in order to control the curing speed when making a duplicate plate, and the heating temperature and heating time, and the cooling temperature and cooling time are selected according to the properties of the duplicate plate material used. do it.

  In the duplicate plate making process, a defoaming process may be performed before filling the replica plate material into the needle-like body 401 in order to improve reproducibility in a fine region. A known defoaming method may be used for the defoaming step. For example, a defoaming method such as vacuum defoaming, centrifugal degassing, and stirring defoaming may be used.

  The method for filling the replica array 403 of the needle-shaped array material is not limited to this, but from the viewpoint of productivity, an imprint method, a hot embossing method, an injection molding method, an extrusion molding method, and a casting method are used. It is preferable to use it.

  In order to improve the peelability of the replication plate 403, a release layer for increasing the release effect may be formed on the surface of the replication plate 403 before filling with the needle array material. As the release layer, for example, a widely known fluorine-based resin can be used. Further, as a method for forming the release layer, a thin film forming method such as a PVD method, a CVD method, a spin coating method, or a dip coating method can be suitably used. By applying the release layer, it is possible to provide the needle-like body having a fine protrusion and the protrusion more stably.

<Example 1>
The method for producing the needle-shaped body of the present invention will be described with reference to an example in which the pitch of the etching mask is wide at the center of the first surface of the substrate and narrow at the end.

  First, a silicon wafer (thickness: 525 μm, diameter 100 mm) 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 with a film thickness of 13 μm using a spray coating method, and the diameter is 100 μm by a photolithography method. A circular dot pattern was formed.

  At this time, the etching masks were arranged in an array. That is, as shown in FIG. 3B, the etching mask is formed so that needles are formed intensively at the four corners of the first surface of the substrate, particularly the first surface. Arranged.

  Next, the etching mask was heated in a clean oven at 150 ° C. for 30 minutes to perform thermal shrinkage. The resist shape after heat shrinkage was hemispherical, and the resist thickness at the center was 20 μm.

  Next, the first 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 acicular array obtained by etching the entire surface of the substrate was observed with a scanning electron microscope. As a result, it was confirmed that a conical needle-like body having a base diameter of about 100 μm, a height of about 220 μm, and a tip angle of about 25 ° was formed reflecting the arrangement of the etching mask.

<Example 2>
Hereinafter, a method for manufacturing the needle-like body array by transfer processing will be described.

  The acicular body array produced in Example 1 was used as an original plate, and a nickel layer having a thickness of 300 nm was formed on the original plate by vapor deposition, and 1 mm of nickel was formed by plating using the nickel layer as a seed layer.

  Next, the original plate was dissolved using an aqueous potassium hydroxide solution having a concentration of 25 wt% and a liquid temperature of 90 ° C. to prepare a duplicate plate made of nickel.

  Using this duplicate plate, maltose, dextran, and polylactic acid were respectively transferred and molded by imprinting. When observed with a scanning electron microscope, it was confirmed that the obtained acicular array had acicular bodies having the same shape as each original plate.

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

The figure which shows an example of the acicular body array according to this invention. The figure which shows an example of the manufacturing method of the acicular body array according to this invention. The figure which shows the example of the arrangement pattern of an etching mask. The figure which shows an example of the manufacturing method of the acicular body array according to this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Acicular body array 2 Base body 3 Acicular body 101, 201 Substrate 102, 202 Etching mask 103 Etching mask (after deformation)
104 Needle-like bodies 401, 404 Needle-like body array 402 Template layer 403 Replica

Claims (3)

A needle-like body array comprising a base and a plurality of needle-like bodies formed on the first surface of the base,
The plurality of needle-like bodies are integrally formed on the first surface of the base body,
The density of the needle-like body varies depending on the portion of the first surface,
The plurality of needles have the same height;
A needle array comprising the substrate and the plurality of needles is formed from a biocompatible biodegradable material selected from maltose, dextran and polylactic acid ; and
The density of the needle-like bodies at the end of the first surface is increased at any location across the outer periphery of the end relative to the density of the needle-like bodies at the center of the first surface. An acicular array characterized by the above. A method for producing a needle-like body array comprising a base and a plurality of needle-like bodies formed on the first surface of the base,
Forming an etching mask having a dense distribution on the first surface of the substrate;
Performing anisotropic etching on the first surface of the substrate to integrally form a plurality of needles having the same height and different densities on the first surface;
With
The density of the needle-like bodies at the end of the first surface is increased at any location across the outer periphery of the end relative to the density of the needle-like bodies at the center of the first surface. A method for manufacturing a needle-shaped body array. It is a manufacturing method of the acicular body array according to claim 2 ,
Furthermore, the manufactured needle-shaped body array is used as a mother mold, and a process for producing a duplicate plate in which the needle-shaped array is inverted from the mother mold to the mother mold;
Performing transfer processing molding using the duplicate plate;
A method of manufacturing an acicular array, comprising:

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